Crystal structure of the influenza virus polymerase pac-pb1n complex and uses thereof

ABSTRACT

Provided are the expression method of influenza virus polymerase PAc-PB1 N  complex, the co-crystallization method of the complex and the three-dimendional structure of the crystal of PAc-PB1 N  complex. Also provided are the compounds binding to the influenza virus polymerase PAc and the expression method of influenza virus polymerase PA N . The three-dimensional structure of the crystal of PAc-PB1 N  complex can be used for screening and designing the drug for the treatment of influenza.

TECHNICAL FIELD

The present invention relates to a method for expression of influenza virus PA and PB1 N-terminal polypeptide in bacteria, purification and crystallization. It also relates to the crystal three-dimensional structure of complex of C-terminal of PA and N-terminal polypeptide of PB1 and its application in drug design.

BACKGROUND ART

Influenza virus have already brought great disaster to human beings (Taubenberger and Morens 2007). Due to lacking enough treating means and frequent variation of the virus itself, the virus remains a threat to human beings. In recent years, frequent and severe avian influenza epidemic situation as well as transmission of avian influenza in human beings has constituted a great threat to health and economics of human beings, so investigation directed to this kind of virus is of great value to protect human health. Avian influenza virus belongs to influenza virus A type, which are all Orthomyxoviridae family members. The virus genome consists of 8 negatively charged single-stranded RNA. Through comparison and analysis of genes of Avian influenza virus origin and other influenza A viruses, it is found that there are sporadic mutations in primary struture, and these mutations result in differential pathogenicity of different influenza viruses. Now, it is considered that influenza virus can encode 11 proteins, wherein the replication of influenza virus genome RNA and mRNA transcription were completed by the RNA polymerase carried by that virus itself, and thus the polymerase has become a potentially important drug target. Recent research suggested that the high pathogenicity of some influenza viruses is directly correlated with the polymerase mutations (Hulse-Post, Franks et al. 2007; Munster, de Wit et 20 al. 2007), further illustrating the necessity of designing drugs aming at this complex. Investigation into this complex is of great significance to reveal the molecular mechanism underlying virus replication and to design drugs aming at this complex. The RNA polymerase is a complex composed of PB1, PB2 and PA subunits, wherein PB1 is a subunit with catalytic activity, PB2 is responsible for acquiring cellular mRNA cap (CAP structure) through a snatching mode as primers of virus mRNA transcription, but PB1 acts as an endonuclease in this process. A temperature sensitive mutant ts53 suggests that PA takes part in the replication process of virus genome, but its specific function is still unclear (Sugiura, Ueda et al. 1975; Kawaguchi, Naito et al. 2005). The polymerase has three kind of RNA activity which is needed in virus synthesis, i.e. mRNA, cRNA and vRNA, respectively. The mRNA synthesis starts from capped oligonucleotide primer and ends at the 15-17 nucleotides from vRNA terminal and a polyA tail is added. Polymerase can synthesize cRNA intermediate of the full-length virus de novo and further synthesize full-length vRNA. Respective subunits of the polymerase can be exprssed by insect cell expression system, thus forming three different complexes, wherein one is a ternary complex containg the three subunits PB1/PB2/PA of polymerase, and the other two are binary complexes: PB1/PB2 and PB1/PA binary complex respectively, but they can not form PB2/PA complex (Honda, Mizumoto et al. 2002). Wherein, 25 amino acids of PB1 N-terminal are sufficient to interact with PA C-terminal, whereas PB1 C-terminal is responsible for the interaction with PB2 N-terminal. A synthetical competive small peptide of PB1 N-terminal can significantly inhibit the activity of virus polymerase. RNA synthesis experiments using dinucleotide ApG as primers indicated that PB1/PA complex can effectively initiate the replication of virus genome RNA, and PB1/PB2 can synthesize virus mRNA in vitro (Honda, Mizumoto et al. 2002), but the recombinant polymerase which was expressed and purified using 293 cell revealed that the three subuits are all necessary for replication and transcription (Deng, Sharps et al. 2006). The idea that PA principally participates the replication process of virus RNA is derived from a finding that a tempreture sensitive mutant (L226P) can result in replication disorder of virus genome under non-permissible temperatures without affecting transcription activity (Kawaguchi, Naito et al. 2005); whereas PB2 is involved in virus mRNA transcription. Further studies found that PA can extensively take part in processes such as transcription, replication and virus stability (Hara, Schmidt et al. 2006). PB1/PA complex can bind the 5′ terminal virus promoter, but only PB1 fails to bind that promoter. Cross-linking experiments indicate that PA can bind vRNA and cRNA promoters (Fodor, Pritlove et al. 1994; Deng, Sharps et al. 2005; Hara, Schmidt et al. 2006)(Fodor 1994, Gonzalez 1999, Jung 2006, Hara 2006), but the specific binding sites are not clear. PA was found to have similar protease activity as chymotrypsins. Sanz-Ezquerro et al. (1996) found that about 250 amino acids at N-terminal are the active region of that protease (Sanz-Ezquerro, Zurcher et al. 1996). But subsequently the studies by Hara et al. (2001) showed that the Serine at position 624 of C-terminal was the active site of PA protease, and the mutation at that site resulted in loss of protease activity, therefore Ser624 may also consiste an active region of that protease (Hara, Shiota et al. 2001). There is still controversy about the effect of PA protease activity on polymerase function. Hara et al. (2006) reported that purified recombinant PA protein can be degraded into two fragments with molecular weight of ˜25 kDa and ˜55 kDa through trypsin hydrolysis (Hara, Schmidt et al. 2006). It is known that three-dimensional structure of protein is of great help to perform rational drug design, so revealing three-dimensional structure of PA is of important value to perform drug design and function studies. In addition, previous studies have not reported the expression and purification of influenza virus protein PA in bacteria, so expression and purification of proteins in bacteria is of important benefit to further explore the function of PA and to perform drug screening, thus saving much time and greatly decreasing job cost and labour intensity.

SUMMARY OF THE INVENTION

The present invention provides a method of separating the wild type or mutant protein of influenza virus polymerase complex subunit PA into N-terminal and C-terminal, and then cloning and expressing them respectively; and a method of expressing, purifying and crystallizating N-terminal of PA; and a method of expressing N-terminal short peptide of wild type or mutant protein of influenza virus polymerase subunit PB1; and a method of co-purification of PA C-terminal and PB1 N-terminal short peptides. The method of expressing and co-purifying the complex of the former 256 amino acids of the N-terminal of PA as well as 257-716 amino acids of C-terminal of PA and the 25 peptides of N-terminal of PB1 according to the invention, crystallization method of the protein complex of PA C-terminal and PB1 N-terminal peptide as well as crystal three-dimensional structure of the resulting complex.

In one aspect, the present invention provides a method of dividing the wild type or mutant protein of influenza virus polymerase complex subunit PA into N-terminal part and C-terminal part as well as cloning and expressing them respectively; and a method of expressing, purifying and crystalling N-terminal of PA; and a method of expressing N-terminal polypeptide of wild type or mutant protein of influenza virus polymerase subunit PB1 and co-purifying the complex of PA C-terminal and PB1 N-terminal short peptides for crystallization. The present invention preferably use prokaryotic cell expression system of E. coli (but other expression systems are not exclued, for example, expression can also be performed in other bacteria or other eukaryotic cells) to express the above-mentioned polypeptide as GST (glutathione-5-transferase) fusion protein, and mix two kind of expression bacteria which express PA C-terminal and PB1 N-terminal short peptide, and further co-purify the protein complex containing above-mentioned PA C-terminal and PB1 N-terminal short peptides from the bacteria, for use in crystallization of protein. According to the expression method of obtaining the former 256 amino acids of N-terminal of influenza virus polymerase subunit PA and 257-716 amino acids of C-terminal of influenza virus polymerase subunit PA through expression in E. coli and the method of obtaining microbial population of E. coli that express the polypeptide within 25 or 48 amino acids of N-terminal of influenza virus protein PB1 that are described in the invention, the methods can express the GST (glutathione-5-transferase)-fused fusion proteins by cloning corresponding genes into pGEX-6p vector.

In another aspect, the present invention provides a method of purifying the complex of PA C-terminal (PAc) and PB1_(N) peptides, comprising: the microbial population expressing the 257-716 amino acids of C-terminal of influenza virus PA and the microbial population expressing a short peptide within 25 or 48 amino acids of the N-terminal of influenza virus PB1 were suspended with buffers respectively, and these two expression bacteria are mixed proportionally to reach a certain molar ratio between the total protein content of GST-PAc and GST-PB1_(N), thus expressing the protein mixture of these two proteins; the protein mixture was purified by affinity column and then cleaved by PreScission protease to cut GST fusion protein; and the complex of PA and PB1 N-terminal peptide through such methods as gel filtration and ion exchange chromatography; and the protein purity is determined by gel electrophoresis.

In another aspect, the present invention provides a method of crystallizing the complex of PAc and PB1_(N) peptide obtained as described above, comprising: the complex of PAc and PB1_(N) peptide is condensed to a concentration of 5-30 mg/ml; the crystal growth condition is screened by gas hanging drop at 4-30° C.; and crystal of the protein complex is obtained.

In another aspect, the present invention provides the crystal of the complex of PAc and PB1_(N) peptides.

In another aspect, the present invention provides crystal three-dimensional structure of the complex of PAc and PB1_(N) peptide, the structure describes interaction mode between PAc and PB1_(N) and corresponding interaction sites, and also describes the composition of secondary structure, peptide chain direction and three-dimensional molecular structure of polypeptide in the complex, wherein X-ray crystal diffraction was performed based on the crystal of the complex of PAc and PB1_(N) peptide to obtain the diffraction data from the protein crystal of the complex of PAc and PB1 N-terminal peptide, and then three-dimensional structure model of the complex of PAc and PB1_(N) peptide was constructed by further performing a structure analysis process with the diffraction data from the protein crystal.

In one embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the C-terminal of the influenza virus polymerase subunit PA-PAc is amino acids from amino acid positions about 201˜about 301 to about 650˜terminal, the N-terminal of influenza virus polymerase subunit PB1-PB1_(N) is a short peptide within the 48 amino acids of the N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein atoms of the crystal three-dimensional structure of the complex have at least part of atomic coordinates listed in table 1, or any structure that has average root mean square deviation (RMSD) smaller than or equal to 1.7 Angstrom with atomic coordinates of main chain carbon backbone of at least 40% amino acids in the crystal three-dimensional structure of complex.

Preferably, the crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has space group of P4(1)2(1)2, and the lattice parameters are about: a=b=122 Angstrom, c=133 Angstrom, α=β=γ=90°.

In one embodiment, the influenza virus is selected from influenza virus A, B and C type, preferably influenza virus A type: A/goose/Guangdong/1/96, A/Brevig Mission/1/1918; influenza virus B type: B/Ann Arbor/1/1966 or influenza virus C type: C/JJ/1950.

In one embodiment, the C-terminal of influenza virus A polymerase subunit PA-PAc consists of the first portion (i.e. it constitutes the mouth section of the crystal structure, as shown in FIG. 4) and the second portion (i.e. it constitutes the head section of the crystal structure, as shown in FIG. 4), wherein the first portion consists of α helix 4, i.e. amino acids fragment of 406-414 positions, α helix 5, i.e. amino acids fragment of 440-450 positions, α helix 8, i.e. amino acids fragment of 583-603 positions, α helix 9, i.e. amino acids fragment of 608-613 positions, α helix 10, i.e. amino acids fragment of 633-649 positions, α helix 11, i.e. amino acids fragment of 653-673 positions, α helix 12, i.e. amino acids fragment of 683-691 positions, α helix 13, i.e. amino acids fragment of 698-714 positions, β sheet 8, i.e. amino acids fragment of 619-623 positions and β sheet 9, i.e. amino acids fragment of 628-631 positions; wherein the second portion mainly consists of β sheet 1, i.e. amino acids fragment of 290-292 positions, β sheet 2, i.e. amino acids fragment of 317-324 positions, β sheet 3, i.e. amino acids fragment of 480-491 positions, β sheet 4, i.e. amino acids fragment of 496-506 positions, β sheet 5, i.e. amino acids fragment of 517-526 positions, β sheet 6, i.e. amino acids fragment of 541-550 positions and β sheet 7, i.e. amino acids fragment of 557-571 positions; wherein the β sheets of the second portion of the C-terminal of PA-PAc is surrounded by α helix 1, i.e. amino acids fragment of 303-311 positions, α helix 2, i.e. amino acids fragment of 331-349 positions, α helix 3, i.e. amino acids fragment of 364-369 positions, α helix 6, i.e. amino acids fragment of 454-475 positions and α helix 7, i.e. amino acids fragment of 572-578 positions, wherein fragments of influenza virus B and C type corresponding to α helixes and β sheets of influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the C-terminal of influenza virus type A polymerase subunit PA-PAc interacts with N-terminal of PB1-PB1_(N) mainly through α helix 8, α helix 10, α helix 11 and α helix 13, preferably through at least one amino acid selected from a group consisting of Leu666 of α helix 11, Phe710 of α helix 13, Val636 of α helix 10, Leu640 of α helix 10, Trp706 of α helix 13 and Gln670 of α helix 11, wherein fragments of influenza virus B and C type corresponding to α helixes of influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIG. 10A, FIG. 10B respectively.

In one embodiment, wherein at least one amino acid selected from the group consisting of Ile621, Gly622, Glu623, Thr618 and Pro620 interacts with the influenza virus polymerase subunit PB1, the Ile621, Gly622, Glu623, Thr618 and Pro620 is in the ring peptide between α helix 9 and α helix 10 of C-terminal of influenza virus A polymerase subunit PA-PAc, wherein fragments of influenza virus B and C type corresponding to α helixes of influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, wherein at least one amino acid selected from the group consisting of Asn647, Gln408, Cys584, Gln587, Gln591, Lys643, Asn647, Ser659, Lys663, Trp699 and Asn703 of the C-terminal of influenza virus A polymerase subunit PA-PAc constitutes “pocket-shape” amino acid sites which bind the influenza virus polymerase subunit PB1_(N), wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, wherein at least one amino acid selected from the group consisting of Trp406, Glu410, Lys461, Glu524, Phe525, Ser526, Lys536, Lys539, Tyr540, Leu563, Tyr564, Arg566 and Lys574 of the C-terminal of influenza virus A polymerase subunit PA-PAc constitutes “big groove” and “channel” structures which bind nucleotide, RNA or other small molecules or proteins, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, amino acid residues of 370˜405 positions of the C-terminal of PA-PAc constitutes a big ring, wherein corresponding fragments of influenza virus B and C type to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, α helix 12 and α helix 13 interact with other proteins, preferably at least one amino acid selected from the group consisting of Ile690, Glu691, Glu692, Cys693 and Asn696 of the α helix 12 and α helix 13 interacts with other proteins.

In one embodiment, at least one amino acid selected from the group consisting of Lys506, Gly507, Arg508, Ser509, His510, Leu511, Arg512, Asn513 and Asp514 interacts with other proteins, wherein His510 constitutes a portion of the polymerase complex RNAse, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, which binds to at least one member selected from the group consisting of α helix 8, α helix 10, α helix 11 and α helix 13 of C-terminal of influenza virus subunit PA-PAc, preferably binds to the member selected from the group consisting of Leu666 in α helix 11, Phe710 in α helix 13, Val636 and Leu640 in α helix 10, Trp706 in α helix 13, Gln670 in α helix 11 of N-terminal of influenza virus subunit PA-PAc, wherein fragments of influenza virus B and C type corresponding to influenza virus A are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to at least one member selected from the group consisting of Ile621, Gly622, Glu623, Thr618 and Pro620 located at the circle peptide between α helix 9 and α helix 10 of the C-terminal of influenza virus polymerase subunit PA-PAc, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to at least one amino acid selected from the group consisting of Asn647, Gln408, Cys584, Gln587, Gln591, Lys643, Asn647, Ser659, Lys663, Trp699 and Asn703 of the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to at least one amino acid selected from the group consisting of Trp406, Glu410, Lys461, Glu524, Phe525, Ser526, Lys536, Lys539, Tyr540, Leu563, Tyr564, Arg566 and Lys574 of the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to amino acids position 370˜405 of the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to helix 12 and α helix 13 of the C-terminal of influenza virus A polymerase subunit PA-PAc, preferably to at least one amino acid selected from the group consisting of Ile690, Glu691, Glu692, Cys693 and Asn696 in α helix 12 and α helix 13, wherein corresponding fragments of influenza virus B and C type to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to at least one amino acid selected from the group consisting of Lys506, Gly507, Arg508, Ser509, His510, Leu511, Arg512, Asn513 and Asp514 located at ring region between sheet β 4 and sheet β 5 in the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate which competes with influenza virus polymerase subunit PB1 for binding PAc, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides an interaction with PAc through the hydrophobic core constituted by the α helix 8, α helix 11, α helix 13 and α helix 10, preferably interaction with PAc through Met595 in α helix 8, Leu666 in α helix 11, Trp706 and Phe710 in α helix 13, Val636 and Val640 in α helix 10, wherein fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate which competes with influenza virus polymerase subunit PB1 for binding PAc, wherein the amino acid sequence of the polypeptide, protein, antibody or immune conjugate comprises at least three amino acids which are identical to amino acids of corresponding position in short PTLLFL motif of the short helix domain constituted by the 5th˜10th residues Pro5, Thr6, Leu7, Leu8, Phe9 and Leu 10 of N-terminal of wild influenza virus polymerase subunit PB1-PB1_(N), when the polypeptide or protein is aligned with the PTLLFL motif.

In one embodiment, the present invention provides a composition comprising above-mentioned polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate.

In one embodiment, the present invention provides use of the above-mentioned composition in manufacturing the medicament used in the treatment of diseases caused by influenza virus.

In one embodiment, the present invention provides a method of expressing and purifying the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), comprising: (a) construct a vector of gene sequence encoding amino acid positions about 201˜about 301 to about 650˜terminal of the C-terminal of influenza virus polymerase subunit PA-PAc, with a tag protein fused or not fused to the vector, prokaryotic cells or eukaryotic cells are transformed with said vector in order to express the PAc with the tag protein; (b) a method similar with that of expressing PAc was used to express the PB1_(N) with or without a tag protein; (c) Proportionally mix the cell expressing influenza virus polymerase subunit PAc obtained from step (a) and the cell expressing amino acids within the 48 amino acids of the N-terminal of influenza virus polymerase subunit PB1 obtained from step (b), the resulting protein is separated through the specifically recognizing by the specific tag, the tag protein is removed from the protein through enzymolysis, the complex of PAc and PB1_(N) is separated, and the concentration of the complex is determined;

The atoms of the Crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has at least 40% atomic coordinates listed in table 1, or atomic coordinates of main chain carbon backbone of at least 40% amino acids in the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to the atomic coordinates listed in table 1.

In one embodiment, the present invention provides a method of expressing and purifying the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the tag protein is selected from GST, Flag-tag, Myc-tag, MBP-tag, specific antibodies; the vector comprises selective marker gene, the proportional mixing in step (c) means that molar ratio of tag protein-PAc and tag protein-PB1_(N) is 0.1:1˜1:0.1, preferably the molar ratio of tag protein-PAc and tag protein-PB1_(N) is 0.5:1˜1:0.5, more preferably the molar ratio of tag protein-PAc and tag protein-PB1_(N) is nearly 1:1; preferably the tag protein is GST, the method recognizing the specific tag is performed through affinity column, the method of removing tag is preformed by enzymolysis with proteinases, the method of separating the complex of PAc and PB1_(N) is preformed through gel filtration or ion-exchange chromatography, the protein concentration is determined through gel electrophoresis.

In one embodiment, the present invention provides a method of expressing and purifying the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the vector is pGEX-6p plasmid vector, and said selective marker gene is penicillin resistance gene, and the proteinase used in step (c) is ProScission proteinase; the restriction site in primers that is employed by the vector is a restriction site selected from a group consisting of SalI and NotI; the restriction site used where gene fragment is inserted is a restriction site selected from a group consisting of SalI and NotI; said gene fragment of C-terminal of influenza virus polymerase subunit PA-PAc is obtained from the genome of influenza virus A type: A/goose/Guangdong/1/96 by polymerase chain reaction (PCR) method; said vector and said inserted gene fragment are treated by corresponding DNA restriction enzyme respectively, such as those selected from a group consisting of BamHI and XhoI, and then the inserted gene and the vector is liagated by T4 DNA ligase, thus transfroming prokaryotic cells such as E. coli to obtain cloned plasimds. The cloned plasmid as described above is transformed into E. coli BL21, the resulting transformed bacteria are cultured and induced by using IPTG, wherein the preferred concentration of IPTG is 0.1 mM to 1 mM, and the cultured bacteria are centrifuged to obtain the microbial population that express said fusion protein.

In one embodiment, the present invention provides a method of co-crystallizing the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), comprising: the protein concentration of the purified complex of PAc and PB1_(N) is condensed to 5-30 mg/ml; the crystal growth condition is screened by gas sitting drop and hanging drop; and crystal of the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) is obtained.

In one embodiment, the present invention provides a method of expressing wild type or mutant protein of N-terminal of PA-PA_(N), wherein PA_(N) is amino acids from positions 1˜ about 50 to about 200˜ about 300, the method comprising: construct a expression vector of gene sequence encoding amino acid positions 1˜ about 50 to about 200˜ about 300 of the N-terminal of influenza virus polymerase subunit PA-PA_(N), with a gene of tag protein fused to the vector, and cells are transformed with the expression vector in order to express the PA_(N) with the maker protein, wherein the N-terminal of PA-PA_(N) has at least 40% sequence identity with the amino acids listed in FIG. 1C.

In one embodiment, the present invention provides a method of expressing wild type or mutant protein of N-terminal of PA-PA_(N), wherein the gene sequence of N-terminal of polymerase subunit PA-PA_(N) is cloned into plasmind vectors for example, a series of pGEX vectors such as pGEX-6p, pGEX-4 T (Amersham Pharmacia), a series of pET vectors (Novagen) and a series of pMAL-c2 (Invitrogen) to express a fusion protein GST-PA_(N) which N-terminal of PA_(N) is fused with GST; the plasmid vector comprises the penicillin resistance gene and the restriction site that is employed by vector when cloning the polypeptide gene of N-terminal of PA-PA_(N) is a restriction site selected from a group consisting of BamHI and XhoI from multiple cloning sites in pGEX-6p; the restriction site used in PA_(N) gene cloning fragment is BamHI and XhoI; gene fragment of PA_(N) protein is amplified from the genome of influenza virus A type: A/goose/Guangdong/1/96 by polymerase chain reaction (PCR) method; the vector and the inserted gene fragment are treated by corresponding DNA restriction enzyme respectively, such as those selected from a group consisting of BamHI and XhoI, and then the inserted gene and the vector is liagated by T4 DNA ligase, thus transfroming E. coli to obtain cloned plasimds. The cloned plasmid as described above is transformed into E. coli BL21, the resulting transformed bacteria are cultured and induced by using 0.1 mM to 1 mM IPTG, and the cultured bacteria are centrifuged to obtain the microbial population that express said fusion protein.

In one embodiment, the present invention provides a method of screening candidate compounds which compete with PB1_(N) for binding PAc, the method comprising: (a) combine PAc to surface of the fixed support; (b) contact the excess tagged PB1_(N) with the fixed PAc; (c) thoroughly elute with eluent in order to remove unbound PB1_(N); (d) contact the candidate compound solutions to be detected with the fixed PAc binding to the PB1_(N) in step (b); (e) thoroughly elute with the eluent in order to obtain solution to be detected; (f) measure concentration of free tagged PB1_(N) in the solution to be detected; (g) calculate the binding capability of the candidate compound to be detected with PAc according to the concentration of free tagged PB1_(N) in the solution.

In one embodiment, the present invention provides a method of screening candidate compounds which compete with PB1_(N) for binding PAc, wherein combining PAc to surface of the fixed support in step (a) is accomplished through covalently crosslinking or through binding PAc with affinity matrix, wherein there is a binding group of affinity matrix on the surface of the fixed support.

In one embodiment, the present invention provides a method of screening candidate compounds which compete with PB1_(N) for binding PAc, wherein the affinity matrix can be other polypeptides such as GST, Flag-tag, Myc-tag, MBP-tag and specific antibody, whereas there is corresponding binding group on the surface of the fixed support.

In one embodiment, the present invention provides a method of screening candidate compounds compete with PB1_(N) for binding PAc, wherein the tagged PB1_(N) polypeptide is selected from the protein tagged with isotope or the protein tagged with other chemical molecule, preferably, the other chemical molecular tag is green fluorescent protein or various fusion polypeptides, eg. binding peroxidase, phosphohydrolase, protien kinase, various group transferase.

In one embodiment, the present invention provides a method of screening candidate compounds which compete with PB1_(N) for binding PAc, wherein the fixed surface can be affinity chromatography columns

In one embodiment, the present invention provides use of the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) in designing and screening polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate used in the treatment of diseases caused by the influenza virus infection.

Drug screening can be performed based on the above method of expressing and purifying PAc protein; the above method of expressing and purifying the complex of PAc and PB1_(N) polypeptide and the above method of obtaining protein crystal, and drug design can be performed based on the three-dimensional structure of PAc and PB1_(N).

In one embodiment, the present invention provides use of the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) in designing and screening polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate used in the treatment of diseases caused by the influenza virus infection, comprising:

design polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to specific portion through computer simulation technology according to coordinates of three-dimensional structure of protein;

search for potential polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to specific portion through computer simulation technology according to coordinates of three-dimensional structure of the protein;

the designed or searched polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate according to coordinates of three-dimensional structure of the protein bind to any subtype of influenza virus polymerase protein which have at least 50% sequence identity with the PAc and the PB1_(N) sequence, binding information is then analyzed;

the designed or searched polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate according to coordinates of three-dimensional structure of the protein bind to any subtype of influenza virus polymerase protein which have at least 50% sequence identity with the PAc and the PB1_(N) sequence, and then crystallization is preformed, the binding information of polypeptide or compound molecule to protein is analyzed through crystal diffraction method;

wherein the polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate that bind to any subtype of influenza virus polymerase protein which had at least 50% sequence identity with the PAc and the PB1_(N) sequence are candidate compounds.

To reveal the role of PA in polymerase and its fine three-dimensional structure, the inventors analyzed the crystal structure with a resolution of 2.9 Angstrom of the complex of a fragment of 257-716 residue in the C-terminal of PA (PAC) and 25 peptides in the N-terminal of PB1 (PB1N). This structure clearly indicates the interaction mode between the C-terminal of PA and N-terminal of PB1 as well as the composition of amino acid residues that participate in the interaction and their relative spatial position; reveals the three-dimensional structure model of the complex of C-terminal of PA and N-terminal of PB1, the composition of secondary structure in that protein, the binding sites of nucleic acid in PA protein molecule, small-molecule channel in PA protein molecule and the charge distribution of PA protein surface, providing structure basis for investigating the role of PA in the complex of virus RNA polymerase, and providing protein crystal platform and three-dimensional platform for designing drugs aming at interaction between PA and PB1 as well as interaction between PA and RNA and other proteins to inhibit the activity of influenza virus polymerase.

It should be noted that the amino acid sequence of corresponding fragments in influenza virus B and C type to α helixes and β sheets of influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively, which is not listed in detail.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B: Sequence of C-terminal of PA and protein sequence of PB1_(N) from three type of influenza virus. FIG. 1A. Sequence alignment of PA protein from three type of influenza virus, wherein A_OURS is sequence of C-terminal of PA protein from influenza virus A type: A/goose/Guangdong/1/96; A_(—)1918 is sequence of PA protein from influenza virus A type: A/Brevig Mission/1/1918, which is the cause of widespread influenza outbreak and a great death event in Europe in 1918; B_(—)1966 is sequence of PA protein from influenza virus B type: B/Ann Arbor/1/1966; C_(—)1950 is sequence of PA protein from influenza virus C type: C/JJ/1950; this result indicates that protein of influenza virus polymerase subunit PA has highly conservative amino acid residues. FIG. 1B. Sequence alignment of PB1_(N) protein from four type of influenza virus, wherein A_OURS, A_(—)1918, B_(—)1966, C_(—)1950 are as described above. In figures, . . . is used to indicate amino acid deletion in corresponding fragments. Specific amino acid positions in specification and claims are illustrated by the example of A_OURS.

FIG. 1C: Sequence of N-terminal of PA protein from three type of influenza virus. In figures, . . . is used to indicate amino acid deletion in corresponding fragments. Specific amino acid positions in specification and claims are illustrated by the example of A_OURS.

FIG. 2: Purification of a polypeptide fragment of the former 256 amino acid in PA N-terminal of influenza virus A type: A/goose/Guangdong/1/96, wherein A shows the peak of purified protein during gel filtration chromatography Superdex-200(Amersham Pharmacia Inc.). B represents electrophoresis result from PA N-terminal of corresponding peak. C is the finally purified protein of PA N-terminal.

FIG. 3: Protein crystallization and diffraction obtained from purified protein of PA N-terminal (1-256 residues), wherein A and B are crystals obtained under different crystallization conditions; and C and D show X-ray diffraction pattern of two protein crystals from PA N-terminal.

FIG. 4: PAc and GST-PB1_(N) protein expressed and purified in E. coli, and interaction experiment between PAc and PB1 N-terminal peptide, and ribbon image of structure of the complex between purified PAc and PB1_(N) polypeptide. A. purified PAc protein, and in vitro interaction experiment between purified PAc and PB1 N-terminal peptide. B. Diagram of three-dimensional structure of the complex between PAc and PB1_(N) polypeptide, which shows a overall structure of chewing wolf's head.

FIG. 5: Overall structure of the complex of C-terminal of PA and N-terminal of PB1, wherein: A. side view of overall structure of the complex of PAc and PB1_(N), to clearly show the direction of protein chain; B. Image in FIG. 5(A) is rotated by 180°, wherein secondary structure is marked, and the two ends of PB1 N-terminal peptide and PAc is indicated by arrows.

FIG. 6: Interaction between PAc and PB1_(N) polypeptide, wherein: A. surface image of PA protein molecule; N-terminal polypeptide of PB1 is illustrated by ribbon image, whereas PA molecule is illustrated by surface charge distribution. B. zoomed to observe that interaction between PA and PB1 is mainly through hydrophobic interaction.

FIG. 7: Surface charge pattern of PA protein molecule, wherein A and B are consistent with the direction of A and B in FIG. 5 respectively.

FIG. 8: Schematic diagrams of big groove and channel present in molecular structure of PAc/PB1_(N) complex. A illustrates the big groove, and some alkaline amino acids residues are marked. B and C are drawings of channel observed from the two sides respectively (rotate 180° about X axis). Some reserved amino acids in or around the channel are marked.

FIG. 9: Illustration of interaction between PA-C and PB1-N, wherein: A. ribbon image of three-dimensional structure of the complex molecule between PA-C and PB1-N polypeptide; B. A surface image of PA protein molecule. N-terminal polypeptide of PB1 is illustrated by ribbon image, whereas PA molecule is illustrated by surface charge distribution. C. part of the complex is zoomed to observe that helix 8, 10, 11 and 13 of PA molecule interac with PB1 polypeptide. D. zoomed to observe interaction between PA and PB1. N-terminal polypeptide of PB1 is illustrated by ribbon image, whereas PA molecule is illustrated by surface charge distribution. The two polypeptides bind mainly through hydrophobic interaction.

FIG. 10: As describded in FIGS. 1A and 1B: Sequence of C-terminal of PA and protein sequence of PB1_(N) from three type of influenza virus. A. Sequence alignment of PA protein from three type of influenza virus, wherein A_OURS is sequence of C-terminal of PA protein from influenza virus A type: A/goose/Guangdong/1/96; A_(—)1918 is sequence of PA protein from influenza virus A type: A/Brevig Mission/1/1918, which is the cause of widespread influenza outbreak and a great death event in Europe in 1918; B_(—)1966 is sequence of PA protein from influenza virus B type: B/Ann Arbor/1/1966; C_(—)1950 is sequence of PA protein from influenza virus C type: C/JJ/1950; this result indicates that protein of influenza virus polymerase subunit PA has highly conservative amino acid residues. B. Sequence alignment of PB1_(N) protein from four type of influenza virus, wherein A_OURS, A_(—)1918, B_(—)1966, C_(—)1950 are as described above. In figures, . . . is used to indicate amino acid deletion in corresponding fragments. Specific amino acid positions in specification and claims are illustrated by the example of A_OURS. The box noted with “Round Loop” indicates big-ring region in the structure, and the other box (unmarked) is a possible nucleic acid binding region. Arrows indicate amino acid residues in PA that participate in binding with PB1 short peptide. Specific amino acid positions in specification and claims are illustrated by the example of A_OURS.

EMBODIMENTS

The present invention provides a method of expressing fragments of wild type or mutant protein of influenza virus polymerase subunit PA, wherein N-terminal part and C-terminal part are expressed and purified in E. coli respectively, including: a method of only using N-terminal of PA for crystallization experiment; a method of expressing and purifying a fragment containing the 257-716 residue in the C-terminal of the PA as well as the wild type and mutant protein of the N-terminal of influenza virus subunit PB1 in E. coli respectively. It also provides a method of crystallizating the complex of C-terminal of PA and N-terminal peptide of PB1, and the crystal structure of complex of PAc/PB1_(N) short peptide obtained therefrom, and drug screening based on these crystallization methods as well as drug design based on these crystal structures.

In one embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the C-terminal of the influenza virus polymerase subunit PA-PAc is amino acids from amino acid positions about 201˜ about 301 to about 650˜ terminal, the N-terminal of influenza virus polymerase subunit PB1-PB1_(N) is a short peptide within the 48 amino acids of the N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein atoms of the crystal three-dimensional structure has at least 40% atomic coordinates listed in table 1, or atomic coordinates of main chain carbon backbone of at least 40% amino acids in the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has an average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to the atomic coordinates listed in table 1.

In one embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the influenza virus is selected from influenza virus A, B and C type, preferably influenza virus A type: A/goose/Guangdong/1/96, A/Brevig Mission/1/1918; influenza virus B type: B/Ann Arbor/1/1966 or influenza virus C type: C/JJ/1950.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the crystal of the complex has space group of P4(1)2(1)2, and the lattice parameters are about: a=b=122 Angstrom, c=133 Angstrom, α=β=γ=90°.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the C-terminal of influenza virus A polymerase subunit PA-PAc consists of the first portion and the second portion, wherein the first portion consists of α helix 4, i.e. amino acids fragment of 406-414 positions, α helix 5, i.e. amino acids fragment of 440-450 positions, α helix 8, i.e. amino acids fragment of 583-603 positions, α helix 9, i.e. amino acids fragment of 608-613 positions, α helix 10, i.e. amino acids fragment of 633-649 positions, α helix 11, i.e. amino acids fragment of 653-673 positions, α helix 12, i.e. amino acids fragment of 683-691 positions, α helix 13, i.e. amino acids fragment of 698-714 positions, β sheet 8, i.e. amino acids fragment of 619-623 positions and β sheet 9, i.e. amino acids fragment of 628-631 positions; wherein the second portion mainly consists of β sheet 1, i.e. amino acids fragment of 290-292 positions, β sheet 2, i.e. amino acids fragment of 317-324 positions, β sheet 3, i.e. amino acids fragment of 480-491 positions, β sheet 4, i.e. amino acids fragment of 496-506 positions, β sheet 5, i.e. amino acids fragment of 517-526 positions, β sheet 6, i.e. amino acids fragment of 541-550 positions and β sheet 7, i.e. amino acids fragment of 557-571 positions; wherein the β sheets of the second portion of the C-terminal of influenza virus polymerase A polymerase subunit PA-PAc is surrounded by α helix 1, i.e. amino acids fragment of 303-311 positions, α helix 2, i.e. amino acids fragment of 331-349 positions, α helix 3, i.e. amino acids fragment of 364-369 positions, α helix 6, i.e. amino acids fragment of 454-475 positions and α helix 7, i.e. amino acids fragment of 572-578 positions, wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the C-terminal of influenza virus A polymerase subunit PA-PAc interacts with N-terminal of PB1-PB1_(N) mainly through α helix 8, α helix 10, α helix 11 and α helix 13, preferably through at least one amino acid selected from a group consisting of Leu666 of α helix 11, Phe710 of α helix 13, Val636 of α helix 10, Leu640 of α helix 10, Trp706 of α helix 13 and Gln670 of α helix 11, wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein at least one amino acid selected from the group consisting of Ile621, Gly622, Glu623, Thr618 and Pro620 interacts with the influenza virus polymerase subunit PB1, the Ile621, Gly622, Glu623, Thr618 and Pro620 is in the ring peptide between α helix 9 and α helix 10 of C-terminal of influenza virus A polymerase subunit PA-PAc, wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein at least one amino acid selected from the group consisting of Asn647, Gln408, Cys584, Gln587, Gln591, Lys643, Asn647, Ser659, Lys663, Trp699 and Asn703 of the C-terminal of influenza virus A polymerase subunit PA-PAc constitutes “pocket” amino acid sites which bind the influenza virus polymerase subunit PB1_(N), wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein at least one amino acid selected from the group consisting of Trp406, Glu410, Lys461, Glu524, Phe525, Ser526, Lys536, Lys539, Tyr540, Leu563, Tyr564, Arg566 and Lys574 of the C-terminal of influenza virus A polymerase subunit PA-PAc constitutes “big groove” and “channel” structures which bind nucleotide, RNA or other small molecules or proteins, wherein amino acids of fragments of influenza virus B and C type corresponding to the influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein amino acid residues of 370-405 positions of the C-terminal of influenza virus A polymerase subunit PA-PAc constitutes a big ring, wherein amino acids of fragments of influenza virus B and C type corresponding to the influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein α helix 12 and α helix 13 of C-terminal of influenza virus polymerase subunit PA-PAc interact with other proteins, preferably at least one amino acid selected from the group consisting of Ile690, Glu691, Glu692, Cys693 and Asn696 of the α helix 12 and α helix 13 interacts with other proteins, and amino acids of fragments of influenza virus B and C type corresponding to the influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In a preferred embodiment, the present invention provides crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein at least one amino acid of C-terminal of influenza virus polymerase subunit PA-PAc that is selected from the group consisting of Lys506, Gly507, Arg508, Ser509, His510, Leu511, Arg512, Asn513 and Asp514 interacts with other proteins, wherein His510 constitutes a portion of the polymerase complex RNAse, and amino acids of fragments of influenza virus B and C type corresponding to the influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In another embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound binding to at least one member selected from the group consisting of α helix 8, α helix 10, α helix 11 and α helix 13 of C-terminal of influenza virus polymerase subunit PA-PAc, wherein the influenza virus is selected from influenza virus A, B and C type, preferably influenza virus A type: A/goose/Guangdong/1/96, A/Brevig Mission/1/1918; influenza virus B type: B/Ann Arbor/1/1966 or influenza virus C type: C/JJ/1950; wherein the polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate preferably bind to the member selected from the group consisting of Leu666 in α helix 11, Phe710 in α helix 13, Val636 and Leu640 in α helix 10, Trp706 in α helix 13, Gln670 in α helix 11 of C-terminal of influenza virus polymerase subunit PA-PAc, wherein amino acids of fragments of influenza virus B and C type corresponding to the influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In another embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to at least one member selected from the group consisting of Ile621, Gly622, Glu623, Thr618 and Pro620 located at the circle peptide between α helix 9 and α helix 10 of the C-terminal of influenza virus polymerase subunit PA-PAc, wherein amino acids of fragments of influenza virus B and C type corresponding to the influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In another embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to at least one amino acid selected from the group consisting of Asn647, Gln408, Cys584, Gln587, Gln591, Lys643, Asn647, Ser659, Lys663, Trp699 and Asn703 of the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In another embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to at least one amino acid selected from the group consisting of Trp406, Glu410, Lys461, Glu524, Phe525, Ser526, Lys536, Lys539, Tyr540, Leu563, Tyr564, Arg566 and Lys574 of the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In another embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to amino acids position 370˜405 of the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In another embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to helix 12 and a helix 13 of the C-terminal of influenza virus A polymerase subunit PA-Pac, preferably to at least one amino acid selected from the group consisting of Ile690, Glu691, Glu692, Cys693 and Asn696 in α helix 12 and α helix 13, wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In another embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate binding to at least one amino acid selected from the group consisting of Lys506, Gly507, Arg508, Ser509, His510, Leu511, Arg512, Asn513 and Asp514 located at ring region between β sheet 4 and β sheet 5 in the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein amino acids of fragments of influenza virus B and C type corresponding to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In another embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate which competes with influenza virus polymerase subunit PB1 for binding PAc.

In a preferred embodiment, the present invention provides the polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate which competes with influenza virus polymerase subunit PB1 for binding PAc predominantly by an interaction with PAc through the hydrophobic core constituted by the α helix 8, α helix 11, α helix 13 and α helix 10, preferably interaction with PAc through Met595 in α helix 8, Leu666 in α helix 11, Trp706 and Phe710 in α helix 13, Val636 and Val640 in α helix 10, wherein amino acids of corresponding fragments of influenza virus B and C type to influenza virus A type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, 10B respectively.

In a preferred embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate which competes with influenza virus polymerase subunit PB1 for binding PAc, wherein the amino acid sequence of the polypeptide or protein comprises at least three amino acids which are identical to amino acids of corresponding position of short PTLLFL motif of the short helix domain constituted by the 5th-10th residues Pro5, Thr6, Leu7, Leu8, Phe9 and Leu10 of N-terminal of wild influenza virus polymerase subunit PB1-PB1_(N), when the polypeptide or protein is aligned with the PTLLFL motif

In another embodiment, the present invention provides a composition comprising above-mentioned polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates, and optionally comprising an carrier and an excipient.

In another embodiment, the present invention provides use of the composition in manufacturing medicaments used in the treatment of diseases caused by influenza virus.

In another embodiment, the present invention provides a method of expressing and purifying the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), comprising:

(a) Construct a vector of gene sequence encoding amino acid positions about 201˜ about 301 to about 650˜ terminal of the C-terminal of influenza virus polymerase subunit PA-PAc, with a tag protein fused or not fused to the vector, prokaryotic cells or eukaryotic cells are transformed with said vector in order to express the PAc with the tag protein;

(b) A method similar with that of expressing PAc was used to express the PB1_(N) with or without a tag;

(c) Proportionally mix cells expressing the influenza virus PAc obtained from step (a) and cells expressing amino acids sequence within the 48 amino acids of the N-terminal of influenza virus PB1 obtained from step (b), the resulting protein is separated through the specifically recognizing the specific tag, the tag protein is removed from the protein through enzymolysis, the complex of PAc and PB1_(N) is separated, the concentration of the complex is determined;

Wherein the atoms of the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has at least 40% atomic coordinates listed in table 1, or atomic coordinates of main chain carbon backbone of at least 40% amino acids in the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to the atomic coordinates listed in table 1.

In a preferred embodiment, wherein the tag protein is selected from GST, Flag-tag, Myc-tag, MBP-tag, specific antibodies; the vector comprises selective marker gene, the Proportional mixing in step (c) means that molar ratio of tag protein-PAc and tag protein-PB1_(N) is 0.1:1˜1:0.1, preferably the molar ratio of tag protein-PAc and tag protein-PB1_(N) is 0.5:1˜1:0.5, more preferably the molar ratio of tag protein-PAc and tag protein-PB1_(N) is nearly 1:1; more preferably the tag protein is GST, the method of recognizing the specific tag is performed through affinity column, the method of removing tag is preformed with a protease, the method of separating the complex of PAc and PB1_(N) is preformed through gel filtration or ion-exchange chromatography, the protein concentration is determined through gel electrophoresis.

In a more preferable embodiment, wherein the procaryotic cell is E coli.

In another embodiment, the present invention provides a method of cocrystallizing the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), comprising:

the protein concentration of the purified complex of PAc and PB1_(N) is condensed to 5-30 mg/ml;

the crystal growth condition is screened by gas sitting drop and hanging drop;

crystal of the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) is obtained.

In another embodiment, the present invention provides a method of expressing wild type or mutant protein of N-terminal of PA-PA_(N), wherein PA_(N) is amino acids from positions 1˜ about 50 to about 200˜ about 300, the method comprising: construct an expression vector of gene sequence encoding amino acid positions 1˜ about 50 to about 200˜ about 300 of the N-terminal of influenza virus polymerase subunit PA-PA_(N), with a gene of tag protein fused or not fused to the vector, and eukaryotic cells or prokaryotic cell are transformed with the vector in order to express the PA_(N) with or without the tag protein, wherein the amino acid sequence of the N-terminal of PA-PA_(N) has at least 40% sequence identity with the amino acids listed in FIG. 1C.

In a preferred embodiment, the procaryotic cell is E coli.

In another embodiment, the present invention provides a method of screening candidate compounds which compete with PB1_(N) for binding PAc, the method comprising:

(a) combine PAc to surface of the fixed support;

(b) contact the excess tagged PB1_(N) with the combined PAc;

(c) thoroughly elute with eluent in order to remove unbound PB1_(N);

(d) contact the candidate compound solutions to be detected with the fixed PAc binding to the PB1_(N);

(e) thoroughly elute with the eluent in order to obtain solution to be detected;

(f) measure concentration of free tagged PB1_(N) in the solution to be detected;

(g) calculate the binding capability of the candidate compound to be detected with PAc according to the concentration of free tagged PB1_(N) in the solution.

In a preferred embodiment, combining PAc to surface of the fixed support in step (a) is accomplished through covalently crosslinking or through binding PAc with affinity matrix, wherein there is a binding group of affinity matrix on the surface of the fixed support.

Preferably, the affinity matrix can be selected from GST, Flag-tag, Myc-tag, MBP-tag and specific antibody, whereas there is corresponding binding group of the affinity matrix on the surface of the fixed support.

Preferably, the tagged PB1_(N) polypeptide is selected from the protein tagged with isotope or the protein tagged with other chemical molecule, preferably, the other chemical molecular tag is green fluorescent protein or various fusion polypeptides.

Preferably, the fixed surface can be affinity chromatography columns

In one embodiment, the present invention provides use of the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) in designing and screening polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates used in the treatment of diseases caused by the influenza virus infection, comprising:

design polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates binding to specific portion through computer simulation technology according to coordinates of three-dimensional structure of protein;

search for potential polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates binding to specific portion through computer simulation technology according to coordinates of three-dimensional structure of the protein;

the designed or searched polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates according to coordinates of three-dimensional structure of the protein bind to any subtype of influenza virus polymerase protein which have at least 50% sequence identity with the PAc and the PB1_(N) sequence, binding information is then analyzed;

the designed or searched polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates according to coordinates of three-dimensional structure of the protein bind to any subtype of influenza virus polymerase protein which have at least 50% sequence identity with the PAc and the PB1_(N) sequence, and then crystallization is preformed, the binding information of polypeptide or compound molecule to protein is analyzed through crystal diffraction method;

wherein the polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates that bind to any subtype of influenza virus polymerase protein which had at least 50% sequence identity with the PAc and the PB1_(N) sequence are candidate compounds.

In one embodiment, the present invention provides structure of the three subunits i.e. PA, PB1, PB2 of any subtype of influenza virus polymerase or the complex of PA, PB1 and PB2, wherein a protein contained in it or a fragment thereof has 40% identical sequence with the PAc protein.

In one embodiment, the present invention provides three-dimensional stereochemical structure of the three subunits i.e. PA, PB1, PB2 of any subtype of influenza virus polymerase or that of the complex of PA, PB1 and PB2, wherein the coordinates of three-dimensional structure in main chain of a protein contained in it or a fragment thereof has an average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to three-dimensional atomic coordinates of a main chain carbon backbone having at least 40% amino acid residues of the PAc protein sequence.

In one embodiment, the present invention provides structure of subunit PA, PB1, PB2 or that of the complex of subunit PA, PB1 and PB2 from any subtype of influenza virus, wherein a protein fragment contained in it has 20% sequcne homology with the fragment of amnio acid 1-11 in the PB1_(N) polypeptide, preferably 40% sequence homology.

In one embodiment, the present invention provides a polypeptide or a small molecule, characterized in that it interacts with any amino acid of the influenza virus subunit PA.

In one embodiment, the present invention provides use of the crystal three-dimensional structure in drug screening and drug design.

In one embodiment, the present invention provides a method of screening a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate which binds to the protein based on crystal three-dimensional structure of PAc and PB1_(N) protein, comprising: obtaining PAc-containing crystal by protein crystallization method, or obtaining the coordinates of crystal three-dimensional structure of the protein complex containing PAc and PB1_(N); wherein the three-dimensional structure contains any structure that has an average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to three-dimensional coordinates of a main chain carbon backbone having at least 40% amino acid residues of the coordinates.

In one embodiment, the present invention provides a method of expressing and purifying the influenza virus subunit PA through expressing PA fragments in bacteria and eukaryotic cell expression systems.

In one embodiment, the present invention provides a polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugate that interacts with amino-acid residues on a protein, wherein the protein has at least 40% identical amino acids with any fragment of α helix 8, 10, 11 and 13 in complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N).

It should be noted that the fragments in influenza virus B and C type corresponding to α helix and β sheet of influenza virus A are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, FIGS. 10B respectively, which will not be listed in detail. The alignment methods of protein or polypeptide sequence that can be used is for example: CLUSTALW (http://www.ebi.ac.uk/Tools/clustalw2/index.html).

Expression and Purification Methods of Influenza Virus PA and PB1 Protein:

The protein sequences encoded by virus gene derived from Avian influenza virus A/goose/Guangdong/1/96 are respectively as follows:

(1) Protein sequence of PA:

MEDFVRQCFNPMIVELAEKAMKEYGEDPKIETNKFAAICTHLEVCFMYS DNIFIDERGESTIIESGDPNALLKHRFEIIEGRDRTMAWTVVNSICNTT GVEKPKFLPDLYDYKENRFIEIGVTRREVHTYYLEKANKIKSEKTHIHI FSFTGEEMATKADYTLDEESRARIKTRLFTIRQEMASRGLWDSFRQSER GEETIEERFEITGTMCRLADQSLPPNFSSLEKFRAYVDGEEPNGCIEGK LSQMSKEVNARIEPFLKTTPRPLRLPDGPPCSQRSKFLLMDALKLSIED PSHEGEGIPLYDAIKCMKTFFGWKEPNIVKPHEKGINPNYLLAWKQVLA ELQDIENEEKIPKTKNMRKTSQLKWALGENMAPEKVDFEDCKDVSDLRQ YDSDEPKPRSLASWIQSEFNKACELTDSSWIELDEIGEDVAPIEHIASM RRNYFTAEVSHCRATEYIMKGVYINTALLNASCAAMDDFQLIPMISKCR TKEGRRKTNLYGFIIKGRSHLRNDTDVVNFVSNIEFSLTDPRLEPHKWE KYCVLEIGDMLLRTAIGQVSRPMFLYVRTNGTSKIKMKWGMEMRRCLLQ SLQQIESMIEAESSVKEKDMTKEFFENKSETWPIGESPKGMEEGSIGKV CRTLLAKSVFNSLYASPQLEGFSAESRKLLLIVQALRDNLEPGTFDLGG LYEAIEECLINDPWVLLNASWFNSFLTHALK; i.e., ( SEQ ID NO: 1 ) Met Glu Asp Phe Val Arg Gln Cys Phe Asn Pro Met  Ile Val Glu Leu Ala Glu Lys Ala Met Lys Glu Tyr  Gly Glu Asp Pro Lys Ile Glu Thr Asn Lys Phe Ala  Ala Ile Cys Thr His Leu Glu Val Cys Phe Met Tyr  Ser Asp Phe His Phe Ile Asp Glu Arg Gly Glu Ser  Thr Ile Ile Glu Ser Gly Asp Pro Asn Ala Leu Leu  Lys His Arg Phe Glu Ile Ile Glu Gly Arg Asp Arg  Thr Met Ala Trp Thr Val Val Asn Ser Ile Cys Asn  Thr Thr Gly Val Glu Lys Pro Lys Phe Leu Pro Asp  Leu Tyr Asp Tyr Lys Glu Asn Arg Phe Ile Glu Ile  Gly Val Thr Arg Arg Glu Val His Thr Tyr Tyr Leu  Glu Lys Ala Asn Lys Ile Lys Ser Glu Lys Thr His  Ile His Ile Phe Ser Phe Thr Gly Glu Glu Met Ala  Thr Lys Ala Asp Tyr Thr Leu Asp Glu Glu Ser Arg  Ala Arg Ile Lys Thr Arg Leu Phe Thr Ile Arg Gln  Glu Met Ala Ser Arg Gly Leu Trp Asp Ser Phe Arg  Gln Ser Glu Arg Gly Glu Glu Thr Ile Glu Glu Arg  Phe Glu Ile Thr Gly Thr Met Cys Arg Leu Ala Asp  Gln Ser Leu Pro Pro Asn Phe Ser Ser Leu Glu Lys  Phe Arg Ala Tyr Val Asp Gly Phe Glu Pro Asn Gly  Cys Ile Glu Gly Lys Leu Ser Gln Met Ser Lys Glu Val Asn Ala Arg Ile Glu Pro Phe Leu Lys Thr Thr Pro Arg Pro Leu Arg Leu Pro Asp Gly Pro Pro Cys  Ser Gln Arg Ser Lys Phe Leu Leu Met Asp Ala Leu  Lys Leu Ser Ile Glu Asp Pro Ser His Glu Gly Glu  Gly Ile Pro Leu Tyr Asp Ala Ile Lys Cys Met Lys Thr Phe Phe Gly Trp Lys Glu Pro Asn Ile Val Lys  Pro His Glu Lys Gly Ile Asn Pro Asn Tyr Leu Leu  Ala Trp Lys Gln Val Leu Ala Glu Leu Gln Asp Ile  Glu Asn Glu Glu Lys Ile Pro Lys Thr Lys Asn Met  Arg Lys Thr Ser Gln Leu Lys Trp Ala Leu Gly Glu  Asn Met Ala Pro Glu Lys Val Asp Phe Glu Asp Cys  Lys Asp Val Ser Asp Leu Arg Gln Tyr Asp Ser Asp  Glu Pro Lys Pro Arg Ser Leu Ala Ser Trp Ile Gln  Ser Glu Phe Asn Lys Ala Cys Glu Leu Thr Asp Ser  Ser Trp Ile Glu Leu Asp Glu Ile Gly Glu Asp Val  Ala Pro Ile Glu His Ile Ala Ser Met Arg Arg Asn  Tyr Phe Thr Ala Glu Val Ser His Cys Arg Ala Thr  Glu Tyr Ile Met Lys Gly Val Tyr Ile Asn Thr Ala  Leu Leu Asn Ala Ser Cys Ala Ala Met Asp Asp Phe  Gln Leu Ile Pro Met Ile Ser Lys Cys Arg Thr Lys  Glu Gly Arg Arg Lys Thr Asn Leu Tyr Gly Phe Ile  Ile Lys Gly Arg Ser His Leu Arg Asn Asp Thr Asp  Val Val Asn Phe Val Ser Met Glu Phe Ser Leu Thr Asp Pro Arg Leu Glu Pro His Lys Trp Glu Lys Tyr  Cys Val Leu Glu Ile Gly Asp Met Leu Leu Arg Thr  Ala Ile Gly Gln Val Ser Arg Pro Met Phe Leu Tyr  Val Arg Thr Asn Gly Thr Ser Lys Ile Lys Met Lys  Trp Gly Met Glu Met Arg Arg Cys Leu Leu Gln Ser  Leu Gln Gln Ile Glu Ser Met Ile Glu Ala Glu Ser  Ser Val Lys Glu Lys Asp Met Thr Lys Glu Phe Phe  Glu Asn Lys Ser Glu Thr Trp Pro Ile Gly Glu Ser  Pro Lys Gly Met Glu Glu Gly Ser Ile Gly Lys Val  Cys Arg Thr Leu Leu Ala Lys Ser Val Phe Asn Ser  Leu Tyr Ala Ser Pro Gln Leu Glu Gly Phe Ser Ala  Glu Ser Arg Lys Leu Leu Leu Ile Val Gln Ala Leu  Arg Asp Asn Leu Glu Pro Gly Thr Phe Asp Leu Gly  Gly Leu Tyr Glu Ala Ile Glu Glu Cys Leu Ile Asn  Asp Pro Trp Val Leu Leu Asn Ala Ser Trp Phe Asn  Ser Phe Leu Thr His Ala Leu Lys. (2) Protein sequence of PB1:

MDVNPTLLFLKVPAQNAISTTFPYTGDPPYSHGTGTGYTMDTVNRTHQY SEKGKWTTNTETGAPQLNPIDGPLPEDNEPSGYAQTDCVLEAMAFLEKS HPGIFENSCLETMEIVQQTRVDKLTQGRQTYDWTLNRNQPAATALANTI EVFRSNGLTANESGRLIDFLKDVMESMDKGEMEIITHFQRKRRVRDNMT KKMVTQRTIGKKKQRLNKRSYLIRALTLNTMTKDAERGKLKRRAIATPG MQIRGFVYFVETLARSICEKLEQSGLPVGGNEKKAKLANVVRKMMTNSQ DTELSFTITGDNTKWNENQNPRMFLAMITYITRNQPEWFRNVLSIAPIM FSNKMARLGKGYMFESKSMKLRTQIPAEMLASIDLKYFNESTRKKIEKI RPLLIDGTASLSPGNIMMGMFNMLSTVLGVSILNLGQKRYTKTTYWWDG LQSSDDFALIVNAPNHEGIQAGVDRFYRTCKLVGINMSKKKSYINRTGT EEFTSFFYRYGFVANFSMELPSFGVSGINESADMSIGVTVIKNNMINND LGPATAQMALQLFIKDYRYTYRCHRGDTQIQTRRSEELKKLWEQTRSKA GLLVSDGGPNLYNIRNLHIPEVCLKWELMDEDYQGRLCNPLNPFVSHKE IESVNNAVVMPAHGPAKSMEYDAVATTHSWIPKRNRSILNTSQRGILED EQMYQKCCNLFEKFFPSSSYRRPVGISSMVEAMVSRARIDARIDFESGR IKKEEFAEIMKICSTIEELRRQK; i.e., ( SEQ ID NO: 2 ) Met Asp Val Asn Pro Thr Leu Leu Phe Leu Lys Val  Pro Ala Gln Asn Ala Ile Ser Thr Thr Phe Pro Tyr  Thr Gly Asp Pro Pro Tyr Ser His Gly Thr Gly Thr  Gly Tyr Thr Met Asp Thr Val Asn Arg Thr His Gln  Tyr Ser Glu Lys Gly Lys Trp Thr Thr Asn Thr Glu  Thr Gly Ala Pro Gln Leu Asn Pro Ile Asp Gly Pro  Leu Pro Glu Asp Asn Glu Pro Ser Gly Tyr Ala Gln  Thr Asp Cys Val Leu Glu Ala Met Ala Phe Leu Glu  Lys Ser His Pro Gly Ile Phe Glu Asn Ser Cys Leu  Glu Thr Met Glu Ile Val Gln Gln Thr Arg Val Asp  Lys Leu Thr Gln Gly Arg Gln Thr Tyr Asp Trp Thr  Leu Asn Arg Asn Gln Pro Ala Ala Thr Ala Leu Ala  Asn Thr Ile Glu Val Phe Arg Ser Asn Gly Leu Thr  Ala Asn Glu Ser Gly Arg Leu Ile Asp Phe Leu Lys  Asp Val Met Glu Ser Met Asp Lys Gly Glu Met Glu  Ile Ile Thr His Phe Gln Arg Lys Arg Arg Val Arg  Asp Asn Met Thr Lys Lys Met Val Thr Gln Arg Thr  Ile Gly Lys Lys Lys Gln Arg Leu Asn Lys Arg Ser  Tyr Leu Ile Arg Ala Leu Thr Leu Asn Thr Met Thr  Lys Asp Ala Glu Arg Gly Lys Leu Lys Arg Arg Ala  Ile Ala Thr Pro Gly Met Gln Ile Arg Gly Phe Val  Tyr Phe Val Glu Thr Leu Ala Arg Ser Ile Cys Glu  Lys Leu Glu Gln Ser Gly Leu Pro Val Gly Gly Asn  Glu Lys Lys Ala Lys Leu Ala Asn Val Val Arg Lys  Met Met Thr Asn Ser Gln Asp Thr Glu Leu Ser Phe Thr Ile Thr Gly Asp Asn Thr Lys Trp Asn Glu Asn  Gln Asn Pro Arg Met Phe Leu Ala Met Ile Thr Tyr  Ile Thr Arg Asn Gln Pro Glu Trp Phe Arg Asn Val  Leu Ser Ile Ala Pro Ile Met Phe Ser Asn Lys Met  Ala Arg Leu Gly Lys Gly Tyr Met Phe Glu Ser Lys  Ser Met Lys Leu Arg Thr Gln Ile Pro Ala Glu Met  Leu Ala Ser Ile Asp Leu Lys Tyr Phe Asn Glu Ser  Thr Arg Lys Lys Ile Glu Lys Ile Arg Pro Leu Leu  Ile Asp Gly Thr Ala Ser Leu Ser Pro Gly Met Met  Met Gly Met Phe Asn Met Leu Ser Thr Val Leu Gly  Val Ser Ile Leu Asn Leu Gly Gln Lys Arg Tyr Thr  Lys Thr Thr Tyr Trp Trp Asp Gly Leu Gln Ser Ser  Asp Asp Phe Ala Leu Ile Val Asn Ala Pro Asn His  Glu Gly Ile Gln Ala Gly Val Asp Arg Phe Tyr Arg  Thr Cys Lys Leu Val Gly Ile Asn Met Ser Lys Lys  Lys Ser Tyr Ile Asn Arg Thr Gly Thr Phe Glu Phe  Thr Ser Phe Phe Tyr Arg Tyr Gly Phe Val Ala Asn  Phe Ser Met Glu Leu Pro Ser Phe Gly Val Ser Gly  Ile Asn Glu Ser Ala Asp Met Ser Ile Gly Val Thr  Val Ile Lys Asn Asn Met Ile Asn Asn Asp Leu Gly  Pro Ala Thr Ala Gln Met Ala Leu Gln Leu Phe Ile  Lys Asp Tyr Arg Tyr Thr Tyr Arg Cys His Arg Gly  Asp Thr Gln Ile Gln Thr Arg Arg Ser Phe Glu Leu Lys Lys Leu Trp Glu Gln Thr Arg Ser Lys Ala Gly  Leu Leu Val Ser Asp Gly Gly Pro Asn Leu Tyr Asn  Ile Arg Asn Leu His Ile Pro Glu Val Cys Leu Lys  Trp Glu Leu Met Asp Glu Asp Tyr Gln Gly Arg Leu  Cys Asn Pro Leu Asn Pro Phe Val Ser His Lys Glu  Ile Glu Ser Val Asn Asn Ala Val Val Met Pro Ala  His Gly Pro Ala Lys Ser Met Glu Tyr Asp Ala Val  Ala Thr Thr His Ser Trp Ile Pro Lys Arg Asn Arg  Ser Ile Leu Asn Thr Ser Gln Arg Gly Ile Leu Glu  Asp Glu Gln Met Tyr Gln Lys Cys Cys Asn Leu Phe  Glu Lys Phe Phe Pro Ser Ser Ser Tyr Arg Arg Pro  Val Gly Ile Ser Ser Met Val Glu Ala Met Val Ser  Arg Ala Arg Ile Asp Ala Arg Ile Asp Phe Glu Ser  Gly Arg Ile Lys Lys Glu Glu Phe Ala Glu Ile Met  Lys Ile Cys Ser Thr Ile Glu Glu Leu Arg Arg Gln   Lys

The gene of influenza virus subunit PA was separated into C-terminal part and N-terminal part, and then the C-terminal part and the N-terminal part were cloned by molecular cloning techniques, wherein the N-terminal part contains the first 256 amino acids and the C-terminal part contains 257-716 amino acids. The two parts were cloned into pGEX-6p vector (from Amersham Pharmacia Inc.) respectively so as to express fusion proteins of N-terminal fused with GST (GST-PA_(N) and GST-PAc). The cloned plasmids were transformed into E. coli BL21 respectively, and E. coli are induced by using 0.1 to 1 mM IPTG(isopropyl-β-thiogalactoside) in BL21 to express these two proteins respectively, thus obtaining respectively expressing bacteria of these two protein, for details see Example 1.

The gene encoding within 48 amino acids of N-terminal of PB1 (including the former 25 amino acids peptide) was also cloned into pGEX-6p vector, so as to express fusion protein of fused GST-PB1 peptide.

Likewise, the short peptide of GST fused the former 25 amino acids or former 48 amino acids of PB1_(N) was expressed respectively. The vectors were transformed into E. coli BL21 in the same way. E. coli were induced by using 0.1 to 1 mM IPTG in BL21 to express proteins, thus obtaining expression bacteria of the protein.

The bacteria that express GST-PA-N were suspended with buffer, lysed and centrifuged to obtain supernatant. Then affinity chromatographic column was used to purify GST-PA-N fusion protein from the supernatant.

The GST-PAc expressing bacteria and the GST-PB1 expressing bacteria were suspended with a buffer (which contains about 20 mM Tris-HCl (pH8.0) and 250 mM NaCl) respectively and mixed with a molar ratio between the protein content of GST-PAc and GST-PB1_(N) is 0.1:1˜1:0.1, preferably the molar ratio between the protein content of GST-PAc and GST-PB1_(N) is 0.5:1˜1:0.5, more preferably the molar ratio between the protein content of GST-PAc and GST-PB1_(N) is near 1:1.

Subsequently, Glutathione-Sepharose affinity column (from Amersham Pharmacia Inc.) was used to purify the GST fusion protein. After enzymolysis with PreScission protease (from Amersham Pharmacia Inc.), the complex of PAc/PB1 short peptide was separated and purified through such methods as gel filtration Superdex-200 and ion exchange chromatography (Q sepharose), wherein complex can be used for further crystallization experiment after determining the protein concentration by SDS-PAGE gel electrophoresis.

Crystallization and Optimization of Protein:

The complex that has been expressed and purified through above methods was condensed to a concentration of 5-30 mg/ml, and crystal growth condition is screened with crystallization reagents (from Hampton Research) by gas hanging drop so as to obtain original crystals under conditions of multiple crystallization reagents.

Through further optimization, crystals with good appearance were obtained in solution containing about 1M sodium acetate with different buffer conditions under pH 4-9, wherein larger triangle-cone crystal was obtained in solution containing about 1-1.3M sodium acetate (Sigma) with different buffers under pH 4-9, and the resolution of said crystal is about 4 Angstrom.

When collecting X-ray diffraction data, the crystal required by diffraction was transferred from hanging drops to about 10 μl corresponding crystallization buffer containing 1.4 M sodium acetate and 10% glycerol (Sigma). After the fluid drops are left open for air dehydration for more than one hour, parent crystal and selenium-containing crystal with a resolution of about 3 Angstrom as well as corresponding X-ray diffraction data were obtained.

Collection of Crystal Data and Structure Analysis:

A set data of parent crystal with a resolution of 2.9 Angstrom from the complex crystal of PA-PB1 N-terminal (this PB1 N-terminal contains 25 amino acids) was first collected by using FR-E X-ray diffractometer (Rigaku) under a wave length 1.5418 Angstrom. Then under wave length of 0.9783 and 0.9785 Angstrom, two sets of data from derivative crystal of selenium atom were collected, i.e. peak and edge, using synchrotron radiometer located at APS, Chicago, USA (station number: SBC 19ID; detection screen: ADSC Q315), the resolution of said crystal is about 3.3 Angstrom. The three sets of data were treated by HKL2000 (Otwinowski 1997) and found to have spacegroup of P4(1)2(1)2. Phase was calculated by multi-wavelength anomalous scattering (Hendrickson 1991), and sas file resulted from treatment was searched for selenium atoms by SHELXD (Sheldrick 1998). The protein itself has 14 methionines, and the inventors found 14 selenium atoms in all. Coordinates of selenium atoms and two sets of data (i.e. Peak and Edge) were input into Program autoSHARP (Vonrhein, Blanc et al. 2007) to calculate phase and to modify the electron density map, and several secondary structures (including α helixes and (β sheets) can be clearly found from the calculated electron density map. Then phase can be expanded by Program CAD, and the phase was expanded to 2.9 Angstrom by collected parent data so as to construct a structure model, wherein the Programs used to construt model are ARP/wARP (Perrakis, Morris et al. 1999) and Phenix (Adams, Grosse-Kunstleve et al. 2002). Automatic model construction performed by these two programs can amount to 60% of the whole structure, and the rest is manually constructed through Program COOT (Emsley and Cowtan 2004).

Finally, the resulting model was modified by Program CNS (Brunger, Adams et al. 1998) and REFMAC5(Murshudov, Vagin et al. 1997) to achieve the protein structure analysis, and the final factor R and factor R-free for modify structure are 0.22 and 0.26 respectively.

Atomic coordinates in crystal structure of protein complex of PAc/PB1_(N) short peptide, see Table 1.

Example 1 Method for Expressing Influenza Virus PA and PB1 Polypeptides

In one embodiment of the present invention, PA was divided into two fragments so as to express former 256 amino acid residues fragments and 257-716 amino acid residues fragments of the PA, respectively, and two gene fragments encoding these two protein polypeptides were cloned into an Escherichia coli expression vector, respectively so as to expressing proteins in a bacteria. The PA N-terminal polypeptides were purified from a PA N-terminal (1-256 amino acids) expressing bacteria and used for protein crystallization. C-terminal of PA expressing bacteria was centrifugally collected for later use so as to be co-purified with the N-terminal of PB1 polypeptides.

Polypeptide containing former 25 or no more than 48 amino acids of the N-terminal of PB1 (not containing first-position methionine) was expressed in the form of GST fusion protein in a bacteria. The influenza virus polymerase protein subunit PA was expressed by fragments in a bacteria or other eukaryotic cells such that at least 50% fragments were part of amino acid fragments of positions 257-716 of the PA protein.

Expression and Purification of N-Terminal of Influenza Virus PA in Escherichia coli

The N-terminal of the influenza virus PA (amino acids 1-256) was cloned into a pGEX-6p vector (from Amersham Pharmacia Inc.) via a molecular cloning technique, the cloning sites thereof being BamHI and XhoI. Expression plasmids with a PA N-terminal gene, obtained by cloning, were transformed into Escherichia coli BL21 for protein expression, such that the bacteria could express the N-terminal (amino terminal) of the PA protein which was connected with the GST fusion protein and has protease cleavage sites cleaved by ProScission protease to further separate a GST protein tag from the target protein-PA polypeptide. IPTG with a final concentration of about 0.1-1 mM was used in the cultured Escherichia coli BL21 cells to induce Escherichia coli in order to obtain the expressing bacteria of said protein. The used vector contained an ampicillin-resistance gene. After the cloning-constructed expression plasmids of the fusion protein were transformed into Escherichia coli such as BL21 (Novagen), bacterium were cultured overnight using bacteria culture media such as LB and so on at 37, and after about 12 hours transferred to a mass culture medium in a proportion of about 1:100, and cultured in a shake flask at 37 until OD is approximately 1.0, and then added 0.1-1 mM IPTG for inducing expression. After about 3 to 6 hours, the bacterium were collected centrifugally, and the collected precipitated bacterium could be stored at −20 to −80 in a refrigerator for later use or be used directly for purification of the PA N-terminal protein.

Expression and Purification of Complex of C-Terminal of Influenza Virus PA and PB1 Polypeptide

The C-terminal (amino acids 257-716) of the influenza virus PA was cloned into a pGEX-6p vector (from Amersham Pharmacia Inc.) via a molecular cloning technique, the cloning sites thereof being BamHI and NhoI. Expression plasmids with a PA C-terminal gene, obtained by cloning, were transformed into Escherichia coli BL21 for protein expression, such that the bacteria could express the N-terminal (amino terminal) of the protein which was connected with the GST fusion protein and has protease cleavage sites cleaved by ProScission protease to further separate a GST protein tag from the target protein-PA polypeptide. IPTG with a final concentration of about 0.1-1 mM was used in the cultured Escherichia coli BL21 cells to induce Escherichia coli in order to obtain the expressing bacteria of said protein. The used vector contained an ampicillin-resistance gene. After the cloning-constructed expression plasmids of the fusion protein were transformed into Escherichia coli such as BL21 (Novagen), bacterium were cultured overnight using bacteria culture media such as LB and so on at 37, and after about 12 hours transferred to a mass culture medium in a proportion of about 1:100, and cultured in a shake flask at 37 until OD is approximately 1.0, and then added 0.1-1 mM IPTG for inducing expression after the culture temperature is lowered to 16. After about 12 to 24 hours, the bacterium were collected centrifugally, and the collected precipitated bacterium could be stored at −20 to −80 in a refrigerator for later use or be used directly for purification.

The gene of the N-terminal of PB1 with no more than 48 amino acids (the inventor had expressed the former 48-amino acid polypeptide and the former 25-amino acid polypeptide of the N-terminal of PB1) was likewise cloned into multiple cloning sites of the pGEX-6p vector, wherein the used cloning sites were BamHI and XhoI, such that the bacteria could express a fusion protein containing GST, there is protease cleavage sites cleaved by ProScission protease in the fusion protein in order to further separate a GST protein tag from the target protein of PB1 polypeptide. The fusion protein of a GST-PB1_(N) peptide was expressed in Escherichia coli BL21 in the same way as the PA fusion protein was expressed above. The resistance gene was ampicillin-resistance gene. The protein expression was carried out at 37° C., and the used inducer was IPTG. Finally, the expressing bacterium were collected centrifugally, used directly for protein purification and could be stored temporarily at −20° C. to −80° C. in a refrigerator.

The centrifugally collected expressing bacteria expressing the GST-PA N-terminal polypeptide was suspended using a buffer solution containing 20 mM Tris-HCl (pH8.0) and 250 mM NaCl or a buffer solution of 1×PBS (pH7.4) phosphoric acid. An ultrasonic breaker was used to break cells. The insoluble precipitation was centrifugally separated and removed in order to collect soluble supernatant. A Glutathione affinity chromatographic column was used to purify the GST-PA-N-terminal polypeptide, and the ProScission protease was further used to enzymolyze the fusion protein into two fragments of GST (glutathione S-transferase) and PA-N. Ion exchange chromatography and gel exclusion chromatography were then used to purify the PA-N protein polypeptide. The protein was concentrated to 5-30 mg/mL for crystal growth.

The expressing bacteria expressing the GST-PA_(C) C-terminal polypeptide and the expressing bacteria expressing the GST-PB1_(N) short peptide were suspended using a buffer solution containing 20 mM Tris-HCl (pH8.0) and 250 mM NaCl or a buffer solution of 1×PBS (pH7.4) phosphoric acid, and then mixed in proportion, such that the molar ratio of the total protein of GST-PA to GST-PB1 was 0.1:1 to 1:0.1, preferably 0.5:1 to 1:0.5, most preferably close to 1:1.

The cell in the mixed bacterial suspension was lysed using ultrasonic wave or other cell lysing methods. An insoluble portion and a soluble portion of the bacterial lysates were centrifugally separated. The supernatant obtained by high speed centrifugation (about 20,000 g) was preliminarily separated using a Glutathione-Sepharose affinity column (from Amersham Pharmacia Inc.) to purify such mixed protein. The protein containing a GST tag could bind to the Glutathione-Sepharose affinity column, while other proteins could not bind to said affinity column. The above mentioned bacterial suspension buffer solution was used to rinse impurity after the protein bound to the affinity column. A suitable amount of ProScission protease (from Amersham Pharmacia Inc.) was used to enzymolyze the mixed GST fusion protein of the affinity column. This process generally needs about 24 hours. Then, the enzymatically cleaved PA_(C) and PB1_(N) proteins were further separated using methods of gel filtration superdex-200 (from Amersham Pharmacia Inc.), Q sepharose ion exchange chromatography (from Amersham Pharmacia Inc.) and so on to purify the PA_(C)/PB1_(N) short peptide complex (the chromatography column comes from Amersham Pharmacia Inc.). The protein purity was determined via SDS-PAGE gel electrophoresis, and the purity generally reached more than 90%. The protein purified by the above steps was concentrated to about 5-30 mg/mL using an evaporating pipe (coming from Millipore Inc.) for a further crystallization experiment.

The person skilled in the art would know that, the N-terminal of influenza virus PA-PA_(N) and the C-terminal of influenza virus PA-PA_(C) as well as the N-terminal of PB1-PB_(N) could be expressed not only in the prokaryotic cell such as Escherichia coli described hereinabove but also in an eukaryotic cell such as insect cells; any other endonuclease, protease cleavage site, and ligase could be used; the target polypeptide to be purified may be fused with other tags such as GST, and the corresponding separating and purifying method was then selected for purification, and finally the tag fused into the target polypeptide was removed. Various change and modification of the present invention as described above fall within the scope of protection of the present invention.

It shall be noted that, the fragments of an α helix and a β sheet of type B or type C influenza corresponding to type A influenza virus are as shown in FIGS. 1A, 1B and 1C as well as FIGS. 10A and 10B, respectively. Herein, the description thereof is omitted.

Example 2 Crystallization of PA_(C)/PB1_(N) Short Peptide Complex

The complex of the PA and PB1 polypeptides expressed and purified with the above method was concentrated to about 5 to 30 mg/mL. A crystallization reagent (from reagent kits such as Screen Kit I/II, Index, and so on from Hampton Research incorporation, etc.) was used in gas sitting drop to screen crystal growth conditions. Upon preliminary screening, the inventor could obtain an original crystal with multiple different crystallization reagents.

Upon further optimization, a crystal with a fairly good appearance was obtained using a solution containing about 1M of sodium acetate in cases of using buffer solutions with different PH values (PH 4-9). A relatively larger triangle-cone crystal was obtained in a sodium acetate buffer solution (PH4-9) with a concentration of 1 to 1.3 M (from Sigma Inc.), the resolution being about 4 Angstrom.

When X-ray diffraction was performed to collect data, crystal needed for the diffraction was transferred from suspension drops to a 10 microliter corresponding crystal buffer solution containing 1.4M sodium acetate and 10% glycerol (from Sigma). The liquid drops were placed in the air for dehydration for more than one hour to obtain a protein crystal with a high resolution, and the resolution of parental and selenium-containing (selenium substituted) protein crystal could reach more than 2.9 Angstrom.

It shall be noted that, the fragments of an α helix and a β sheet of type B or type C influenza corresponding to type A influenza virus are as shown in FIGS. 1A, 1B and 1C as well as FIGS. 10A and 10B, respectively. Herein, the description thereof is omitted.

Example 3 Crystal Structure of PA_(C)/PB1_(N) Short Peptide Complex

A set data of parent crystal with a resolution of 2.9 Angstrom from the complex crystal of PA-PB1 N-terminal (this PB1 N-terminal contains 25 amino acids) was first collected by using FR-E X-ray diffractometer (Rigaku) under a wave length 1.5418 Angstrom. Then under wave length of 0.9783 and 0.9785 Angstrom, two sets of data from derivative crystal of selenium atom were collected, i.e. peak and edge, using synchrotron radiometer located at APS, Chicago, USA (station number: SBC 19ID; detection screen: ADSC Q315), the resolution of said crystal is about 3.3 Angstrom. The three sets of data were treated by HKL2000 (Otwinowski 1997) and found to have spacegroup of P4(1)2(1)2. Phase was calculated by multi-wavelength anomalous scattering (Hendrickson 1991), and sas file resulted from treatment was searched for selenium atoms by SHELXD (Sheldrick 1998). The protein itself has 14 methionines, and the inventors found 14 selenium atoms in all. Coordinates of selenium atoms and two sets of data (i.e. Peak and Edge) were input into Program autoSHARP (Vonrhein, Blanc et al. 2007) to calculate phase and to modify the electron density map, and several secondary structures (including α helixes and β sheets) can be clearly found from the calculated electron density map. Then phase can be expanded by Program CAD, and the phase was expanded to 2.9 Angstrom by collected parent data so as to construct a structure model, wherein the Programs used to construt model are ARP/wARP (Perrakis, Morris et al. 1999) and Phenix (Adams, Grosse-Kunstleve et al. 2002). Automatic model construction performed by these two programs can amount to 60% of the whole structure, and the rest is manually constructed through Program COOT (Emsley and Cowtan 2004).

Finally, the resulting model was modified by Program CNS (Brunger, Adams et al. 1998) and REFMAC5(Murshudov, Vagin et al. 1997) to achieve the protein structure analysis, and the final factor R and factor R-free for modify structure are 0.23 and 0.26 respectively.

Example 4 Crystallization of N-Terminal of PA

The PA N-terminal polypeptide complex expressed and purified by the above method was concentrated to about 5 to 30 mg/mL. A crystal agent (kits such as Screen Kit I/II, Index, and so on from Hampton Research Incorporation, etc.) was used in gas sitting drop to screen crystal growth conditions. Upon preliminary screening, the inventor obtained an original crystal with different crystal agents.

For further optimization, a crystal well diffracted by an X-ray was obtained from a solution containing about 20% PEG 8000 or 20% PEG 3350 and 0.1 M magnesium chloride or 0.1 M magnesium acetate in a case of using a MES buffer solution with PH 6.5 (all the used regents came from Sigma Inc.) (see A and B crystal pictures and C and D diffraction pictures in FIG. 3). The X-ray diffracting resolution of the obtained crystal is about 2 to 4 Angstrom.

Example 5 Method for Screening Small Molecules Competing with PB1_(N) for Binding to PA_(C)

During a process of screening a small molecular medicament capable of disintegrating the PA_(C)/PB1_(N) short peptide complex, the PB1_(N) short peptide gene was fused with a gene expressing GFP (green fluorescent protein). The PB1_(N) short peptide protein fused with GFP was expressed as an indicator molecule during a small molecular compound disintegrating a protein complex. The PB1 short peptide gene fragment was connected to the GFP gene fragment using a molecular cloning method so as to express PB1 small peptide fusion protein of which one N-terminal or C-terminal was connected with GFP.

Method 1: a complex of PA C-terminal fusion protein with the N-terminal fused GST, viz. GST-PA_(C) fusion protein, and GFP-PB1_(N) short peptide fusion protein was expressed with the above method of expressing and purifying the C-terminal of PA and the PB1 short peptide.

The complex of the GST-PA_(C) fusion protein and the GFP-PB1_(N) short peptide fusion protein flew through and bound to the Glutathione affinity column Since said complex contained the GFP protein, the GFP-PB1_(N) fusion protein binding to GST-PA_(C) enabled the affinity column to show a green color after GST-PA_(C) bound to the affinity column. The affinity column binding with the complex protein of GST-PA_(C) and GFP-PB1_(N) was rinsed sufficiently with a buffer solution to thoroughly elute and remove unbound proteins. Then, a mixture of small molecular compounds to be screened flew through the affinity column (said mixture should not contain Glutathione or other eluted compounds for detaching GST from the affinity column). If the mixture contained small molecules substituted for the PB1_(N) polypeptide to bind to the PA_(C), part of the GFP-PB1_(N) polypeptide fusion protein binding to PAc was replaced and eluted. The eluted solution flowing out showed a green color due to containing said GFP fusion protein when observed under a fixed wavelength fluorescent microscope. The small molecules were further sequentially separated and purified from the mixture, and the components substituted for the PB1_(N) polypeptide were traced by the above green GFP protein tracing method to finally determine a small molecular compound interfering with the binding of PA to the PB1 small peptide. In the above method, besides using GST as an affinity matrix, other polypeptides such as Flag-tag, Myc-tag, MBP (Maltose binding protein)-tag, specific antibody, etc. could be used as combining groups of affinity matrix. Correspondingly, the affinity chromatographic column needs a corresponding affinity matrix, for example, if the Flag-tag was used, an antibody against the Flag-tag (e.g. an anti-flag monoclonal antibody from Sigma Inc.) was used to be fixed to the affinity chromatographic column as a gel medium binding to the Flag. The compound molecules binding to PA and replacing a PB1 small peptide (specific structure) could be determined via methods such as mass spectrometry, etc.

Method 2: PA_(C) was purified separately (fusion protein or non-fusion protein) and covalently crosslinked to a gel medium by chemical crosslinking, but protein was not denatured. GFP-PB1_(N) flew through the covalently binding gel column GFP-PB1_(N) bound to the PA_(C) protein such that the gel column presents a green fluorescent light of GFP. The solution of the small molecular mixture flew through the gel column, if a compound substituted for GFP-PB1_(N) to bind to PA_(C) was present, the GFP-PB1_(N) fusion protein was eluted. The eluent showed a green color by stimulation of a specific-wavelength light, and the compound molecules substituted for GFP-PB1_(N) bound to the PA_(C) molecules of the gel column. A buffer solution was used to elute the gel column to remove impurities, and urea and the like was then used to denature PA_(C) in order that the small molecules binding thereto were eluted. Methods of mass spectrometry and the like were used to analyze small molecules binding to PA to obtain structural information of the small molecules. The compound may be a small molecular medicament capable of disintegrating the PA_(C)/PB1_(N) short peptide complex.

Example 6 Method of Using Crystal Three-Dimensional Structure of PA_(C)/PB1_(N) Complex to Design and Screen Various Polypeptides, Proteins, or Inorganic or Organic Compounds for Treating Diseases Caused by Influenza Virus Infection

A crystal three-dimensional structure of a complex of the C-terminal of influenza virus polymerase subunit PA-PA_(C) and the N-terminal of influenza virus polymerase subunit PB1-PB1_(N) was used to design and screen various polypeptides, proteins, or inorganic or organic compounds for treating diseases caused by influenza virus infection. The specific steps are as follows: polypeptides and compound molecules binding to specific portion were designed through computer stimulation technology according to coordinates of three-dimensional structure of protein; potential polypeptides and compound molecules binding to specific portion were searched for through computer stimulation technology according to coordinates of three-dimensional structure of protein; the polypeptides and compound molecules designed or searched according to the coordinates of three-dimensional structure of protein bound to any type of influenza virus polymerase protein which has at least 50% sequence identity with the PA_(C) and PB1_(N) sequences, and binding information was then analysed; the polypeptides and compound molecules designed or searched according to the coordinates of three-dimensional structure of protein bound to any type of influenza virus polymerase protein which has at least 50% sequence identity with the PA_(C) and the PB1_(N) sequences, and then crystallized; and the binding information of the polypeptides or compound molecules to protein is analyzed through a crystal diffraction method.

Example 7 Designing and Screening Small Peptides Using Crystal Three-Dimensional Structure of PA_(C)/PB1_(N) for Treating Diseases Caused by Influenza Virus Infection

Upon verification by experiment, a short peptide containing M1, D2, V3, N4, P5, T6, L7, L8, F9, L10, and K11 bound to the C-terminal of PA. The inventors cloned gene encoding PB1_(N) polypeptide containing the first-position M1 to the eleventh-position K11 into a pFEX-6p vector, purified said GST-PB1_(N) fusion protein, and used the fusion protein fixed to the affinity chromatographic gel column to bind to PA-C in a solution through an in vitro binding experiment. The inventors found that said fusion protein maintained the PB1_(N)'s capability of binding to PA-C.

Using the same experimental method, the inventors found that a fusion protein containing M1, D2, V3, N4, P5, T6, L7, L8, F9, L10, K11, V12 and p13 also maintained the PB1_(N)'s capability of binding to PA-C. Thus, these two short peptides had a capacity of binding to PA-C to make themselves potential polypeptide medicaments interfering with influenza virus polymerase activity or models for further medicament design.

Likewise, the selected polypeptide having at least three amino acid sequence alignment identical with the above polypeptide might be a potential polypeptide medicament interfering with influenza virus polymerase activity.

The structure of subunits PA, PB1, PB2 or the complex of PA, PB1 and PB2 of any type of influenza virus polymerase contains one protein or one fragment thereof having at least 40% sequences identical with those of the PA_(C) protein.

In the structure of subunits PA, PB1, PB2 or the complex of PA, PB1 and PB2 of any type of influenza virus polymerase, at least 40% coordinates of main chain carbon backbone of three-dimensional structure of one protein or one fragment thereof has average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to the atomic coordinates of PA_(C).

In the structure of subunit PA, PB1, PB2 or the complex of PA, PB1 and PB2 of any type of influenza virus polymerase, the protein fragment has 40% sequence identity of 2-12 amino acid fragments of the PB1_(N) polypeptide.

Any polypeptide or small molecule that interacts with key amino acids of the influenza virus subunit PA is included in the invention.

The structure is used in medicament screening and medicament designing.

A method for screening a compound or polypeptide binding to a protein based on the three-dimensional structure of the PA_(C) and PB1_(N) comprises: obtaining a crystal of the complex of PA_(C) and PB1_(N) proteins by protein crystallization, wherein the crystal of the complex protein has a spacegroup of P4(1)2(1)2, and the crystal cell parameters are: a=b=122 Angstrom, c=133 Angstrom, and α=β=γ=90°; obtaining the coordinate of the three-dimensional structure of the complex of the PA_(C) and PB1_(N) proteins by an X-ray diffracting crystal technique, wherein any structure containing at least 40% amino acid residues of which coordinates of main chain carbon backbone have average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to said coordinate is included.

A method of expressing and purifying influenza virus subunit PA comprises expressing PA in segments in a bacteria or a eukaryotic expressing system, and the method is used to express and purify any protein fragments which has 40% sequence identity with PA.

In a preferred embodiment, the PA_(C)/PB1_(N) complex is used in designing and screening polypeptides, proteins, compounds, or medicaments in the treatment of diseases caused by influenza virus infection.

In a preferred embodiment, polypeptides for treating diseases caused by the influenza virus infection comprises polypeptides interacting with the above complex, at least one of the α helix or β sheet, and at least one amino acid site.

In a preferred embodiment, proteins for treating diseases caused by the influenza virus infection comprises proteins interacting with the above complex, at least one of the α helix or β sheet, and at least one amino acid site.

In a preferred embodiment, compounds for treating diseases caused by the influenza virus infection comprises compounds interacting with the above complex, at least one of the α helix or β sheet, and at least one amino acid site.

In a preferred embodiment, a pharmaceutical composition comprises the above polypeptides, proteins, or compounds.

The pharmaceutical composition of the present invention generally includes one carrier or excipient. An antibody and/or immune conjugate are dissolved in a pharmaceutically acceptable carrier, wherein an aqueous carrier is preferred. Many types of aqueous carriers can be applied, e.g. buffer saline, etc. These solutions are sterilized and generally free from undesired substances. These components can be disinfected through a conventional, well-known disinfecting technique. These components may include auxiliary substances required by physiological conditions, such as a buffering agent adjusting PH, toxicity regulator, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The fusion proteins of these components vary greatly in concentration mainly depending on the selected administration manner, the liquid amount and viscosity required by a patient, body weight, etc.

Therefore, about 1.2 to 1200 μg of one typical pharmaceutical immunotoxin component in the present invention shall be applied daily for brain administration. One typical component for treating neoplasms of breast, ovary and lung via intravenous administration shall be applied to one patient 0.1 to 10 mg per day. The dosage of 0.1 to 100 mg per day for one person may be allowed, especially in a case that the medicament is administrated to a closed position without entering blood circulation or a lymphatic system, for example, it is administrated to a body cavity or an organ lacuna. The actual procedures for preparing applicable medical components are understood or acquired by the person skilled in the art and are described in detail in some publications, e.g. Remington's PHARMACETUTICAL SCIENCE, 19^(th) ed., Mack Publishing Company, Easton, Pa. (1995).

The components of the present invention can be used for a treatment. In treatment application, the components are applied to a patient suffering from a certain disease (for example, glioblastoma, breast cancer, ovarian cancer, and lung cancer), the dosage of which shall be enough to at least alleviate or partially control said disease and the complications thereof. The dosage enough to complete these tasks is called as “therapeutically effective dosage”. The applied effective dosage depends on illness severity and patient's general health conditions. The effective dosage of the component can achieve subjectively-recognized alleviation of a certain symptom or objective improvement recorded by a clinician or other qualified observer.

Whether to be administrate once only or for several times depends on desired and tolerated dose and frequency by a patient. Nevertheless, an adequate amount of the immunotoxin shall be provided to treat a patient effectively. Preferably, the medical dosage might be administrated only once or administrated periodically until a certain therapy efficacy or an adverse reaction inhibits continuation of the treatment. Generally, these dosages are enough to treat or improve disease conditions without incurring unbearable toxicity for a patient.

The immune conjugates of the present invention can be prepared into gastrointestinal sustained release formulations (e.g. an implant, an oil injection, or a microparticle system). A protein delivery system can be fully understood by referring to Banga, A. J., THERAPEUTIC PEPTIDES AND PROTEINS: FORMULATION, PROCESSING, AND DELIVERY SYSTEMS, Technomic Publishing Company, Inc., Lancaster, Pa., (1995). The microparticle system includes microspheres, particles, microcapsules, nano-microcapsules, nano-microspheres, and nano-particles. The microcapsule uses therapeutic protein as a core. In globules, therapeutic substances are dispersed in the particles. Particles, microspheres, and microcapsues which are smaller than about 1 μm are generally called as nano-microparticles, nano-spheres, and nano-microcapsules. Capillary vessels are about 5 μm in diameter. Therefore, only nano-particles are intravenously administrated. The microparticles are about 100 μm in diameter and are intravenously and intramuscularly administrated. Examples are Kreuter, J., COLLOIDAL DRUG DELIVERY SYSTEMS, J. Kreuter, ed., Marcel Dekker, Inc., New York, N.Y., pp. 219-342 (1994); and Tice&Tabibi, TREATISE ON CONTROLLED DRUG DELIVERY, A. Kydonieus, ed., Marcel Dekker, Inc. New York, N.Y., pp. 315-339, (1992), both of which are cited herein.

Polymers can be used for ion controlled release of immune conjugate components in the present invention. Multiple degradable and nondegradable polymers for drug controlled release are well-known in the art (Langer, R., Accounts Chem. Res. 26:537-542 (1993)), for example, a retarding polymer polaxamer 407 is viscous and flowable at low temperature, but is formed as a semisolid gel at body temperature, and is proved to be an effective carrier for forming and delivering continuously recombinant interleukin-2 and urease (Johnston etc., Pharm. Res. 9:425-434 (1992)) and Pec etc., J. Parent. Sci. Tech. 44(2):58-65 (1990)). Likewise, hydroxyapatite can be used as a microcarrier for protein controlled release (Ijntema etc., Int. J. Pharm. 112:215-224 (1994)), while liposome is used for controlled release and targeting transport processes of a liplid-coated medicament (Betageri, etc., LIPOSOME DRUG DELIVERY SYSTEMS, Technomic Publishing Co., Inc., Lancaster, Pa. (1993)). Many other therapeutic protein controlled release systems have been known, for example, U.S. Pat. Nos. 5,055,303, 5,188,837, 4,235,871, 4,501,728, 4,837,028, 4,957,735, 5,019,369, 5,055,303, 5,514,670, 5,413,797, 5,268,164, 5,004,697, 4,902,505, 5,506,206, 5,271,961, 5,254,342, and 5,534,496, any of which is cited herein.

Experimental Results

The atomic coordinate of the structure of the complex of PA_(C) and PB1_(N) is shown in the following Table 1.

TABLE 1 Remark DATE 2008-01-29 TIME 15:31:51 CST +0800 (1201591911.23 s) Remark  3 HIGH RESOLUTION SCOPE (angstrom): 2.899 Remark  3 LOW RESOLUTION SCOPE (angstrom): 45.184 Remark  3 INTEGRITY OF DATA (%): 99.29 Remark  3 NUMBER OF REFLECTIONS: 22964 Remark  3 R VALUE  (WORKING + TEST SET): 0.2329 Remark  3 R VALUE   (WORKING SET): 0.2313 Remark  3 FREE R VALUE     :0.2621 Remark  3 FREE R VALUE TEST SET SIZE  (%):5.12 Remark  3 Data Number used by the FREE R   :1176 Remark  3 ERROR ESTIMATES Remark 3 COORDINATE ERROR (MAXIMUM-LIKELIHOOD BASED) 0.36 Remark 3 PHASE ERROR (DEGREES, MAXIMUM-LIKELIHOOD BASED) 26.77 Remark  3  element count occupies Remark  3  C 2316 2316.00 Remark  3  S  28  28.00 Remark  3  O 729 728.50 Remark  3  N 609 609.00 Remark  3 TOTAL  3682  3681.50 Remark  3 Remark  3  ERROR with ideal coordinate Remark  3 RMSD MAX COUNT Remark  3 BOND   : 0.003 0.046 3703 Remark  3 ANGLE : 0.746 8.143 4994 Remark  3 CHIRALITY: 0.059 0.437  551 Remark  3 PLANARITY:  0.003  0.025   635 Remark  3 DIHEDRAL:   18.490   84.485  1412 Remark  3 The least non-bond distance: 2.355 occupies X Y Z factor_(temp) Atom Atom 1 N ILE A 257 91.537 8.970 33.916 1.00 120.40 N Atom 2 CA ILE A 257 90.592 8.158 34.672 1.00 128.69 C Atom 3 CB ILE A 257 90.300 6.814 33.966 1.00 130.96 C Atom 4 CG1 ILE A 257 89.450 7.047 32.712 1.00 123.59 C Atom 5 CD1 ILE A 257 88.942 5.776 32.059 1.00 118.76 C Atom 6 CG2 ILE A 257 89.601 5.847 34.914 1.00 122.29 C Atom 7 C ILE A 257 91.090 7.920 36.099 1.00 117.70 C Atom 8 O ILE A 257 90.293 7.804 37.031 1.00 115.24 O Atom 9 N GLU A 258 92.409 7.859 36.266 1.00 116.30 N Atom 10 CA GLU A 258 93.009 7.761 37.595 1.00 123.54 C Atom 11 CB GLU A 258 94.530 7.892 37.498 1.00 119.91 C Atom 12 CG GLU A 258 95.178 6.762 36.703 1.00 112.24 C Atom 13 CD GLU A 258 96.441 7.191 35.978 1.00 112.51 C Atom 14 OE1 GLU A 258 96.533 6.950 34.756 1.00 102.19 O Atom 15 OE2 GLU A 258 97.337 7.775 36.624 1.00 102.43 O Atom 16 C GLU A 258 92.393 8.812 38.525 1.00 121.13 C Atom 17 O GLU A 258 92.644 10.007 38.377 1.00 119.88 O Atom 18 N PRO A 259 91.585 8.349 39.493 1.00 114.15 N Atom 19 CA PRO A 259 90.548 9.104 40.206 1.00 110.56 C Atom 20 CB PRO A 259 89.519 8.015 40.557 1.00 117.90 C Atom 21 CG PRO A 259 90.143 6.678 40.122 1.00 108.56 C Atom 22 CD PRO A 259 91.590 6.939 39.906 1.00 107.70 C Atom 23 C PRO A 259 90.959 9.796 41.508 1.00 109.05 C Atom 24 O PRO A 259 90.207 10.646 41.985 1.00 101.59 O Atom 25 N PHE A 260 92.115 9.440 42.061 1.00 112.64 N Atom 26 CA PHE A 260 92.461 9.740 43.459 1.00 110.07 C Atom 27 CB PHE A 260 93.825 9.126 43.796 1.00 118.03 C Atom 28 CG PHE A 260 94.761 9.054 42.623 1.00 117.55 C Atom 29 CD1 PHE A 260 94.893 7.880 41.899 1.00 110.10 C Atom 30 CE1 PHE A 260 95.749 7.808 40.819 1.00 118.42 C Atom 31 CZ PHE A 260 96.485 8.918 40.447 1.00 119.59 C Atom 32 CE2 PHE A 260 96.361 10.095 41.157 1.00 109.72 C Atom 33 CD2 PHE A 260 95.501 10.161 42.239 1.00 117.37 C Atom 34 C PHE A 260 92.434 11.207 43.924 1.00 101.28 C Atom 35 O PHE A 260 93.404 11.679 44.523 1.00 99.58 O Atom 36 N LEU A 261 91.332 11.918 43.693 1.00 110.37 N Atom 37 CA LEU A 261 91.197 13.265 44.260 1.00 110.86 C Atom 38 CB LEU A 261 91.310 14.373 43.206 1.00 83.41 C Atom 39 CG LEU A 261 92.630 15.117 43.435 1.00 75.60 C Atom 40 CD1 LEU A 261 92.957 16.095 42.325 1.00 74.55 C Atom 41 CD2 LEU A 261 92.605 15.826 44.785 1.00 73.35 C Atom 42 C LEU A 261 90.035 13.487 45.239 1.00 106.98 C Atom 43 O LEU A 261 89.563 14.609 45.422 1.00 100.30 O Atom 44 N LYS A 262 89.581 12.396 45.847 1.00 106.50 N Atom 45 CA LYS A 262 89.099 12.431 47.225 1.00 99.64 C Atom 46 CB LYS A 262 90.200 13.043 48.102 1.00 87.94 C Atom 47 CG LYS A 262 91.600 12.580 47.736 1.00 84.96 C Atom 48 CD LYS A 262 92.638 13.623 48.095 1.00 83.60 C Atom 49 CE LYS A 262 92.770 13.777 49.602 1.00 75.13 C Atom 50 NZ LYS A 262 93.106 12.475 50.253 1.00 78.69 N Atom 51 C LYS A 262 87.785 13.153 47.523 1.00 100.82 C Atom 52 O LYS A 262 87.001 13.488 46.632 1.00 94.80 O Atom 53 N THR A 263 87.573 13.366 48.819 1.00 99.01 N Atom 54 CA THR A 263 86.483 14.167 49.342 1.00 84.52 C Atom 55 CB THR A 263 86.065 13.675 50.739 1.00 92.19 C Atom 56 OG1 THR A 263 87.201 13.707 51.614 1.00 89.70 O Atom 57 CG2 THR A 263 85.530 12.248 50.673 1.00 93.60 C Atom 58 C THR A 263 86.993 15.597 49.467 1.00 88.22 C Atom 59 O THR A 263 86.826 16.244 50.500 1.00 87.38 O Atom 60 N THR A 264 87.640 16.076 48.411 1.00 91.46 N Atom 61 CA THR A 264 88.228 17.413 48.398 1.00 85.52 C Atom 62 CB THR A 264 89.071 17.635 47.127 1.00 83.35 C Atom 63 OG1 THR A 264 90.110 16.653 47.069 1.00 86.29 O Atom 64 CG2 THR A 264 89.691 19.022 47.130 1.00 75.97 C Atom 65 C THR A 264 87.197 18.539 48.541 1.00 81.66 C Atom 66 O THR A 264 87.427 19.494 49.289 1.00 75.55 O Atom 67 N PRO A 265 86.066 18.437 47.817 1.00 74.49 N Atom 68 CA PRO A 265 85.014 19.454 47.924 1.00 74.11 C Atom 69 CB PRO A 265 83.877 18.861 47.093 1.00 71.63 C Atom 70 CG PRO A 265 84.569 18.028 46.077 1.00 74.33 C Atom 71 CD PRO A 265 85.759 17.440 46.776 1.00 69.08 C Atom 72 C PRO A 265 84.557 19.668 49.362 1.00 73.62 C Atom 73 O PRO A 265 84.188 18.709 50.037 1.00 73.69 O Atom 74 N ARG A 266 84.594 20.917 49.815 1.00 71.81 N Atom 75 CA ARG A 266 84.154 21.279 51.156 1.00 69.16 C Atom 76 CB ARG A 266 85.153 22.245 51.794 1.00 66.29 C Atom 77 CG ARG A 266 85.305 23.551 51.034 1.00 64.77 C Atom 78 CD ARG A 266 86.031 24.593 51.861 1.00 63.22 C Atom 79 NE ARG A 266 86.266 25.811 51.092 1.00 68.05 N Atom 80 CZ ARG A 266 85.398 26.814 50.994 1.00 71.11 C Atom 81 NH1 ARG A 266 84.230 26.744 51.617 1.00 72.62 N Atom 82 NH2 ARG A 266 85.697 27.885 50.273 1.00 63.93 N Atom 83 C ARG A 266 82.785 21.943 51.081 1.00 75.68 C Atom 84 O ARG A 266 82.339 22.329 50.000 1.00 73.21 O Atom 85 N PRO A 267 82.112 22.087 52.232 1.00 77.49 N Atom 86 CA PRO A 267 80.838 22.811 52.230 1.00 74.00 C Atom 87 CB PRO A 267 80.375 22.712 53.688 1.00 72.07 C Atom 88 CG PRO A 267 81.104 21.529 54.246 1.00 70.88 C Atom 89 CD PRO A 267 82.433 21.527 53.556 1.00 74.87 C Atom 90 C PRO A 267 81.041 24.273 51.846 1.00 70.24 C Atom 91 O PRO A 267 82.057 24.869 52.205 1.00 72.02 O Atom 92 N LEU A 268 80.091 24.837 51.109 1.00 68.84 N Atom 93 CA LEU A 268 80.122 26.258 50.803 1.00 66.24 C Atom 94 CB LEU A 268 79.014 26.621 49.816 1.00 62.15 C Atom 95 CG LEU A 268 78.992 25.877 48.482 1.00 59.79 C Atom 96 CD1 LEU A 268 77.667 26.099 47.763 1.00 64.25 C Atom 97 CD2 LEU A 268 80.149 26.314 47.613 1.00 63.20 C Atom 98 C LEU A 268 79.951 27.039 52.099 1.00 66.63 C Atom 99 O LEU A 268 79.316 26.565 53.038 1.00 69.53 O Atom 100 N ARG A 269 80.526 28.234 52.153 1.00 67.41 N Atom 101 CA ARG A 269 80.440 29.054 53.353 1.00 69.87 C Atom 102 CB ARG A 269 81.817 29.608 53.727 1.00 66.44 C Atom 103 CG ARG A 269 82.745 28.549 54.299 1.00 77.44 C Atom 104 CD ARG A 269 84.209 28.931 54.176 1.00 86.20 C Atom 105 NE ARG A 269 85.080 27.820 54.557 1.00 93.54 N Atom 106 CZ ARG A 269 86.393 27.792 54.359 1.00 87.58 C Atom 107 NH1 ARG A 269 87.001 28.818 53.780 1.00 84.19 N Atom 108 NH2 ARG A 269 87.098 26.735 54.740 1.00 76.10 N Atom 109 C ARG A 269 79.417 30.172 53.196 1.00 69.09 C Atom 110 O ARG A 269 79.525 31.014 52.302 1.00 66.44 O Atom 111 N LEU A 270 78.415 30.161 54.068 1.00 64.18 N Atom 112 CA LEU A 270 77.352 31.159 54.028 1.00 68.05 C Atom 113 CB LEU A 270 75.995 30.518 54.344 1.00 62.77 C Atom 114 CG LEU A 270 75.332 29.702 53.229 1.00 60.46 C Atom 115 CD1 LEU A 270 76.223 28.561 52.763 1.00 59.74 C Atom 116 CD2 LEU A 270 73.983 29.168 53.687 1.00 61.40 C Atom 117 C LEU A 270 77.641 32.324 54.977 1.00 65.51 C Atom 118 O LEU A 270 78.282 32.144 56.013 1.00 62.64 O Atom 119 N PRO A 271 77.163 33.525 54.617 1.00 66.71 N Atom 120 CA PRO A 271 77.402 34.771 55.357 1.00 64.01 C Atom 121 CB PRO A 271 76.628 35.813 54.544 1.00 64.36 C Atom 122 CG PRO A 271 76.475 35.222 53.192 1.00 63.59 C Atom 123 CD PRO A 271 76.362 33.747 53.402 1.00 68.19 C Atom 124 C PRO A 271 76.849 34.757 56.776 1.00 67.61 C Atom 125 O PRO A 271 75.874 34.060 57.056 1.00 71.15 O Atom 126 N ASP A 272 77.477 35.528 57.658 1.00 72.04 N Atom 127 CA ASP A 272 76.918 35.821 58.970 1.00 71.75 C Atom 128 CB ASP A 272 78.031 36.028 59.997 1.00 89.42 C Atom 129 CG ASP A 272 78.540 34.723 60.577 1.00 100.84 C Atom 130 OD1 ASP A 272 77.717 33.806 60.794 1.00 94.50 O Atom 131 OD2 ASP A 272 79.762 34.619 60.822 1.00 108.66 O Atom 132 C ASP A 272 76.096 37.093 58.843 1.00 76.85 C Atom 133 O ASP A 272 76.172 37.784 57.827 1.00 80.23 O Atom 134 N GLY A 273 75.317 37.409 59.871 1.00 80.11 N Atom 135 CA GLY A 273 74.535 38.633 59.873 1.00 79.17 C Atom 136 C GLY A 273 73.094 38.407 60.282 1.00 78.11 C Atom 137 O GLY A 273 72.708 37.286 60.608 1.00 78.88 O Atom 138 N PRO A 274 72.286 39.477 60.269 1.00 75.96 N Atom 139 CA PRO A 274 70.856 39.354 60.564 1.00 74.11 C Atom 140 CB PRO A 274 70.318 40.767 60.300 1.00 71.18 C Atom 141 CG PRO A 274 71.505 41.661 60.373 1.00 72.28 C Atom 142 CD PRO A 274 72.657 40.846 59.878 1.00 74.52 C Atom 143 C PRO A 274 70.221 38.364 59.598 1.00 78.24 C Atom 144 O PRO A 274 70.748 38.171 58.499 1.00 76.47 O Atom 145 N PRO A 275 69.107 37.735 60.000 1.00 79.44 N Atom 146 CA PRO A 275 68.408 36.789 59.124 1.00 71.22 C Atom 147 CB PRO A 275 67.212 36.340 59.973 1.00 71.46 C Atom 148 CG PRO A 275 67.600 36.655 61.385 1.00 69.92 C Atom 149 CD PRO A 275 68.434 37.887 61.300 1.00 72.01 C Atom 150 C PRO A 275 67.923 37.483 57.856 1.00 66.65 C Atom 151 O PRO A 275 67.565 38.661 57.902 1.00 66.44 O Atom 152 N CYS A 276 67.928 36.765 56.738 1.00 61.03 N Atom 153 CA CYS A 276 67.427 37.307 55.481 1.00 64.32 C Atom 154 CB CYS A 276 67.692 36.330 54.337 1.00 63.67 C Atom 155 SG CYS A 276 66.977 34.690 54.596 1.00 65.48 S Atom 156 C CYS A 276 65.934 37.603 55.586 1.00 64.10 C Atom 157 O CYS A 276 65.242 37.060 56.449 1.00 62.47 O Atom 158 N SER A 277 65.439 38.458 54.699 1.00 63.64 N Atom 159 CA SER A 277 64.046 38.879 54.753 1.00 60.63 C Atom 160 CB SER A 277 63.959 40.351 55.147 1.00 60.71 C Atom 161 OG SER A 277 64.595 41.161 54.176 1.00 60.49 O Atom 162 C SER A 277 63.331 38.665 53.423 1.00 63.02 C Atom 163 O SER A 277 63.963 38.580 52.368 1.00 65.56 O Atom 164 N GLN A 278 62.005 38.585 53.488 1.00 63.80 N Atom 165 CA GLN A 278 61.174 38.420 52.303 1.00 57.94 C Atom 166 CB GLN A 278 59.697 38.355 52.697 1.00 57.85 C Atom 167 CG GLN A 278 58.735 38.136 51.536 1.00 59.11 C Atom 168 CD GLN A 278 59.004 36.843 50.789 1.00 62.32 C Atom 169 OE1 GLN A 278 58.254 35.875 50.912 1.00 61.13 O Atom 170 NE2 GLN A 278 60.087 36.817 50.018 1.00 61.31 N Atom 171 C GLN A 278 61.403 39.574 51.337 1.00 56.85 C Atom 172 O GLN A 278 61.604 40.713 51.758 1.00 57.72 O Atom 173 N ARG A 279 61.381 39.276 50.042 1.00 59.21 N Atom 174 CA ARG A 279 61.580 40.300 49.019 1.00 63.43 C Atom 175 CB ARG A 279 63.068 40.498 48.741 1.00 58.78 C Atom 176 CG ARG A 279 63.714 39.337 48.021 1.00 55.98 C Atom 177 CD ARG A 279 65.047 39.744 47.438 1.00 58.76 C Atom 178 NE ARG A 279 65.402 38.891 46.311 1.00 68.48 N Atom 179 CZ ARG A 279 65.122 39.176 45.044 1.00 65.33 C Atom 180 NH1 ARG A 279 64.483 40.299 44.738 1.00 56.96 N Atom 181 NH2 ARG A 279 65.484 38.339 44.080 1.00 60.65 N Atom 182 C ARG A 279 60.851 39.955 47.724 1.00 61.68 C Atom 183 O ARG A 279 61.148 40.508 46.664 1.00 53.66 O Atom 184 N SER A 280 59.907 39.025 47.813 1.00 58.43 N Atom 185 CA SER A 280 59.081 38.678 46.669 1.00 53.89 C Atom 186 CB SER A 280 58.317 37.384 46.932 1.00 58.53 C Atom 187 OG SER A 280 57.534 37.491 48.108 1.00 66.07 O Atom 188 C SER A 280 58.113 39.823 46.405 1.00 56.48 C Atom 189 O SER A 280 57.879 40.653 47.283 1.00 59.54 O Atom 190 N LYS A 281 57.567 39.880 45.195 1.00 59.61 N Atom 191 CA LYS A 281 56.658 40.959 44.815 1.00 58.47 C Atom 192 CB LYS A 281 56.296 40.855 43.335 1.00 63.40 C Atom 193 CG LYS A 281 55.346 41.934 42.855 1.00 68.09 C Atom 194 CD LYS A 281 54.826 41.618 41.464 1.00 74.78 C Atom 195 CE LYS A 281 54.082 42.798 40.868 1.00 78.19 C Atom 196 NZ LYS A 281 54.957 43.995 40.730 1.00 87.89 N Atom 197 C LYS A 281 55.390 40.934 45.662 1.00 64.74 C Atom 198 O LYS A 281 54.975 41.953 46.214 1.00 61.14 O Atom 199 N PHE A 282 54.774 39.760 45.748 1.00 62.08 N Atom 200 CA PHE A 282 53.606 39.566 46.595 1.00 58.02 C Atom 201 CB PHE A 282 52.376 39.212 45.754 1.00 55.39 C Atom 202 CG PHE A 282 52.650 38.209 44.668 1.00 58.20 C Atom 203 CD1 PHE A 282 52.772 38.612 43.349 1.00 62.35 C Atom 204 CE1 PHE A 282 53.026 37.692 42.348 1.00 62.43 C Atom 205 CZ PHE A 282 53.163 36.352 42.662 1.00 63.79 C Atom 206 CE2 PHE A 282 53.047 35.941 43.975 1.00 58.77 C Atom 207 CD2 PHE A 282 52.792 36.867 44.969 1.00 56.46 C Atom 208 C PHE A 282 53.883 38.485 47.632 1.00 57.85 C Atom 209 O PHE A 282 54.906 37.803 47.572 1.00 56.07 O Atom 210 N LEU A 283 52.980 38.346 48.595 1.00 54.72 N Atom 211 CA LEU A 283 53.120 37.326 49.624 1.00 52.75 C Atom 212 CB LEU A 283 52.069 37.516 50.720 1.00 55.49 C Atom 213 CG LEU A 283 52.121 38.824 51.511 1.00 55.91 C Atom 214 CD1 LEU A 283 51.019 38.844 52.557 1.00 53.24 C Atom 215 CD2 LEU A 283 53.484 39.007 52.163 1.00 50.75 C Atom 216 C LEU A 283 52.978 35.953 48.988 1.00 55.54 C Atom 217 O LEU A 283 52.348 35.811 47.941 1.00 53.96 O Atom 218 N LEU A 284 53.568 34.944 49.619 1.00 58.94 N Atom 219 CA LEU A 284 53.520 33.586 49.092 1.00 52.63 C Atom 220 CB LEU A 284 54.933 33.031 48.918 1.00 53.20 C Atom 221 CG LEU A 284 55.799 33.855 47.961 1.00 57.03 C Atom 222 CD1 LEU A 284 57.176 33.231 47.771 1.00 50.50 C Atom 223 CD2 LEU A 284 55.091 34.041 46.621 1.00 54.76 C Atom 224 C LEU A 284 52.681 32.677 49.988 1.00 55.51 C Atom 225 O LEU A 284 51.463 32.618 49.848 1.00 58.23 O Atom 226 N MET A 285 53.327 31.982 50.916 1.00 55.47 N Atom 227 CA MET A 285 52.614 31.073 51.810 1.00 53.47 C Atom 228 CB MET A 285 53.599 30.197 52.582 1.00 58.57 C Atom 229 CG MET A 285 54.464 30.957 53.575 1.00 55.03 C Atom 230 SD MET A 285 55.677 29.887 54.378 1.00 64.78 S Atom 231 CE MET A 285 54.618 28.823 55.360 1.00 58.58 C Atom 232 C MET A 285 51.724 31.823 52.791 1.00 57.38 C Atom 233 O MET A 285 50.812 31.247 53.383 1.00 65.33 O Atom 234 N ASP A 286 52.000 33.111 52.961 1.00 59.98 N Atom 235 CA ASP A 286 51.288 33.925 53.933 1.00 51.26 C Atom 236 CB ASP A 286 52.240 34.943 54.552 1.00 54.72 C Atom 237 CG ASP A 286 53.502 34.302 55.089 1.00 57.96 C Atom 238 OD1 ASP A 286 53.437 33.659 56.159 1.00 57.26 O Atom 239 OD2 ASP A 286 54.562 34.445 54.443 1.00 56.96 O Atom 240 C ASP A 286 50.100 34.639 53.307 1.00 56.00 C Atom 241 O ASP A 286 49.349 35.327 53.999 1.00 59.93 O Atom 242 N ALA A 287 49.930 34.476 51.997 1.00 57.81 N Atom 243 CA ALA A 287 48.835 35.127 51.280 1.00 56.63 C Atom 244 CB ALA A 287 48.961 34.879 49.786 1.00 52.92 C Atom 245 C ALA A 287 47.478 34.650 51.791 1.00 57.56 C Atom 246 O ALA A 287 47.338 33.512 52.230 1.00 63.14 O Atom 247 N LEU A 288 46.484 35.529 51.741 1.00 57.00 N Atom 248 CA LEU A 288 45.125 35.170 52.122 1.00 55.42 C Atom 249 CB LEU A 288 44.749 35.813 53.455 1.00 62.57 C Atom 250 CG LEU A 288 43.303 35.603 53.921 1.00 58.43 C Atom 251 CD1 LEU A 288 43.108 34.184 54.414 1.00 49.90 C Atom 252 CD2 LEU A 288 42.942 36.599 55.008 1.00 58.53 C Atom 253 C LEU A 288 44.158 35.641 51.052 1.00 56.81 C Atom 254 O LEU A 288 44.185 36.805 50.654 1.00 58.00 O Atom 255 N LYS A 289 43.300 34.736 50.593 1.00 59.73 N Atom 256 CA LYS A 289 42.341 35.058 49.543 1.00 56.64 C Atom 257 CB LYS A 289 42.313 33.950 48.486 1.00 54.20 C Atom 258 CG LYS A 289 43.673 33.599 47.909 1.00 57.79 C Atom 259 CD LYS A 289 43.554 32.571 46.793 1.00 56.56 C Atom 260 CE LYS A 289 43.268 31.183 47.338 1.00 63.87 C Atom 261 NZ LYS A 289 44.463 30.585 47.998 1.00 66.79 N Atom 262 C LYS A 289 40.932 35.258 50.095 1.00 58.06 C Atom 263 O LYS A 289 40.454 34.470 50.911 1.00 61.12 O Atom 264 N LEU A 290 40.279 36.324 49.648 1.00 57.12 N Atom 265 CA LEU A 290 38.844 36.484 49.823 1.00 56.50 C Atom 266 CB LEU A 290 38.513 37.904 50.274 1.00 54.88 C Atom 267 CG LEU A 290 39.082 38.345 51.623 1.00 55.95 C Atom 268 CD1 LEU A 290 38.807 39.822 51.853 1.00 53.24 C Atom 269 CD2 LEU A 290 38.519 37.504 52.759 1.00 52.12 C Atom 270 C LEU A 290 38.212 36.195 48.468 1.00 63.90 C Atom 271 O LEU A 290 38.527 36.859 47.483 1.00 70.79 O Atom 272 N SER A 291 37.336 35.198 48.403 1.00 66.46 N Atom 273 CA SER A 291 36.862 34.731 47.101 1.00 73.98 C Atom 274 CB SER A 291 37.495 33.380 46.753 1.00 69.69 C Atom 275 OG SER A 291 37.218 32.413 47.749 1.00 82.37 O Atom 276 C SER A 291 35.346 34.648 46.933 1.00 71.81 C Atom 277 O SER A 291 34.590 34.642 47.903 1.00 65.73 O Atom 278 N ILE A 292 34.926 34.591 45.673 1.00 77.20 N Atom 279 CA ILE A 292 33.527 34.445 45.302 1.00 77.17 C Atom 280 CB ILE A 292 32.901 35.809 44.972 1.00 66.61 C Atom 281 CG1 ILE A 292 33.663 36.480 43.828 1.00 69.00 C Atom 282 CD1 ILE A 292 33.195 37.898 43.525 1.00 76.10 C Atom 283 CG2 ILE A 292 32.894 36.703 46.197 1.00 63.22 C Atom 284 C ILE A 292 33.433 33.545 44.071 1.00 84.27 C Atom 285 O ILE A 292 34.417 32.907 43.687 1.00 82.37 O Atom 286 N GLU A 293 32.254 33.500 43.453 1.00 96.02 N Atom 287 CA GLU A 293 32.063 32.758 42.205 1.00 93.08 C Atom 288 CB GLU A 293 30.810 31.886 42.291 1.00 88.37 C Atom 289 CG GLU A 293 30.595 31.220 43.648 1.00 100.57 C Atom 290 CD GLU A 293 31.694 30.231 44.029 1.00 111.87 C Atom 291 OE1 GLU A 293 31.366 29.049 44.275 1.00 126.15 O Atom 292 OE2 GLU A 293 32.879 30.630 44.093 1.00 103.21 O Atom 293 C GLU A 293 31.974 33.686 40.986 1.00 90.56 C Atom 294 O GLU A 293 32.410 33.341 39.883 1.00 89.86 O Atom 295 N ILE A 302 35.653 43.080 35.367 1.00 86.17 N Atom 296 CA ILE A 302 35.821 44.327 36.107 1.00 97.26 C Atom 297 CB ILE A 302 34.501 45.112 36.211 1.00 97.26 C Atom 298 CG1 ILE A 302 33.835 45.227 34.837 1.00 93.64 C Atom 299 CD1 ILE A 302 32.498 45.942 34.862 1.00 96.26 C Atom 300 CG2 ILE A 302 34.752 46.490 36.810 1.00 93.36 C Atom 301 C ILE A 302 36.355 44.062 37.509 1.00 92.13 C Atom 302 O ILE A 302 35.581 43.829 38.440 1.00 88.17 O Atom 303 N PRO A 303 37.688 44.105 37.659 1.00 90.36 N Atom 304 CA PRO A 303 38.402 43.801 38.903 1.00 84.21 C Atom 305 CB PRO A 303 39.795 44.373 38.647 1.00 83.95 C Atom 306 CG PRO A 303 39.968 44.254 37.173 1.00 86.75 C Atom 307 CD PRO A 303 38.610 44.493 36.576 1.00 88.05 C Atom 308 C PRO A 303 37.789 44.451 40.140 1.00 81.80 C Atom 309 O PRO A 303 37.493 43.749 41.104 1.00 84.37 O Atom 310 N LEU A 304 37.610 45.767 40.116 1.00 79.27 N Atom 311 CA LEU A 304 37.071 46.479 41.271 1.00 84.47 C Atom 312 CB LEU A 304 36.983 47.976 40.991 1.00 87.18 C Atom 313 CG LEU A 304 38.265 48.766 41.234 1.00 87.84 C Atom 314 CD1 LEU A 304 37.985 50.237 41.039 1.00 95.99 C Atom 315 CD2 LEU A 304 38.799 48.500 42.633 1.00 83.86 C Atom 316 C LEU A 304 35.707 45.950 41.691 1.00 86.61 C Atom 317 O LEU A 304 35.432 45.794 42.881 1.00 84.35 O Atom 318 N TYR A 305 34.850 45.685 40.712 1.00 86.70 N Atom 319 CA TYR A 305 33.539 45.124 40.998 1.00 89.33 C Atom 320 CB TYR A 305 32.743 44.921 39.706 1.00 94.36 C Atom 321 CG TYR A 305 31.411 44.238 39.917 1.00 97.01 C Atom 322 CD1 TYR A 305 30.366 44.895 40.556 1.00 94.75 C Atom 323 CE1 TYR A 305 29.149 44.274 40.754 1.00 99.89 C Atom 324 CZ TYR A 305 28.963 42.980 40.309 1.00 107.94 C Atom 325 OH TYR A 305 27.751 42.354 40.501 1.00 112.22 O Atom 326 CE2 TYR A 305 29.984 42.307 39.671 1.00 104.17 C Atom 327 CD2 TYR A 305 31.198 42.936 39.478 1.00 100.81 C Atom 328 C TYR A 305 33.698 43.804 41.745 1.00 85.14 C Atom 329 O TYR A 305 33.054 43.571 42.768 1.00 86.38 O Atom 330 N ASP A 306 34.575 42.949 41.235 1.00 79.13 N Atom 331 CA ASP A 306 34.838 41.663 41.865 1.00 81.52 C Atom 332 CB ASP A 306 35.673 40.780 40.937 1.00 83.26 C Atom 333 CG ASP A 306 34.933 40.408 39.664 1.00 87.46 C Atom 334 OD1 ASP A 306 33.799 40.896 39.464 1.00 91.24 O Atom 335 OD2 ASP A 306 35.486 39.624 38.863 1.00 89.32 O Atom 336 C ASP A 306 35.545 41.840 43.205 1.00 80.16 C Atom 337 O ASP A 306 35.298 41.095 44.155 1.00 81.79 O Atom 338 N ALA A 307 36.429 42.829 43.274 1.00 76.33 N Atom 339 CA ALA A 307 37.161 43.117 44.499 1.00 74.77 C Atom 340 CB ALA A 307 38.102 44.300 44.295 1.00 72.36 C Atom 341 C ALA A 307 36.191 43.395 45.641 1.00 71.76 C Atom 342 O ALA A 307 36.313 42.826 46.726 1.00 69.25 O Atom 343 N ILE A 308 35.223 44.267 45.384 1.00 72.91 N Atom 344 CA ILE A 308 34.237 44.635 46.390 1.00 76.02 C Atom 345 CB ILE A 308 33.356 45.798 45.905 1.00 81.11 C Atom 346 CG1 ILE A 308 34.196 47.071 45.779 1.00 72.28 C Atom 347 CD1 ILE A 308 33.495 48.199 45.064 1.00 86.00 C Atom 348 CG2 ILE A 308 32.184 46.015 46.854 1.00 72.78 C Atom 349 C ILE A 308 33.366 43.445 46.791 1.00 73.57 C Atom 350 O ILE A 308 33.099 43.235 47.972 1.00 72.60 O Atom 351 N LYS A 309 32.929 42.661 45.812 1.00 69.57 N Atom 352 CA LYS A 309 32.133 41.476 46.115 1.00 74.77 C Atom 353 CB LYS A 309 31.599 40.820 44.839 1.00 78.28 C Atom 354 CG LYS A 309 30.575 41.672 44.105 1.00 85.98 C Atom 355 CD LYS A 309 29.443 40.831 43.521 1.00 100.58 C Atom 356 CE LYS A 309 29.946 39.804 42.512 1.00 113.59 C Atom 357 NZ LYS A 309 28.821 39.020 41.914 1.00 107.16 N Atom 358 C LYS A 309 32.920 40.470 46.949 1.00 69.11 C Atom 359 O LYS A 309 32.348 39.749 47.771 1.00 68.26 O Atom 360 N CYS A 310 34.231 40.424 46.734 1.00 72.90 N Atom 361 CA CYS A 310 35.102 39.552 47.514 1.00 67.98 C Atom 362 CB CYS A 310 36.477 39.429 46.856 1.00 62.27 C Atom 363 SG CYS A 310 36.528 38.310 45.444 1.00 65.00 S Atom 364 C CYS A 310 35.242 40.056 48.946 1.00 66.63 C Atom 365 O CYS A 310 35.174 39.281 49.898 1.00 59.77 O Atom 366 N MET A 311 35.438 41.361 49.092 1.00 60.90 N Atom 367 CA MET A 311 35.581 41.955 50.412 1.00 62.78 C Atom 368 CB MET A 311 35.983 43.428 50.309 1.00 64.52 C Atom 369 CG MET A 311 37.326 43.653 49.638 1.00 66.16 C Atom 370 SD MET A 311 37.827 45.382 49.638 1.00 70.15 S Atom 371 CE MET A 311 38.294 45.600 51.353 1.00 63.04 C Atom 372 C MET A 311 34.283 41.810 51.192 1.00 62.65 C Atom 373 O MET A 311 34.296 41.707 52.420 1.00 61.94 O Atom 374 N LYS A 312 33.164 41.796 50.475 1.00 65.90 N Atom 375 CA LYS A 312 31.858 41.672 51.114 1.00 69.11 C Atom 376 CB LYS A 312 30.729 41.965 50.122 1.00 70.01 C Atom 377 CG LYS A 312 30.544 43.437 49.780 1.00 65.98 C Atom 378 CD LYS A 312 29.065 43.762 49.618 1.00 80.79 C Atom 379 CE LYS A 312 28.835 45.139 49.006 1.00 84.10 C Atom 380 NZ LYS A 312 28.820 45.085 47.514 1.00 83.82 N Atom 381 C LYS A 312 31.657 40.294 51.746 1.00 64.33 C Atom 382 O LYS A 312 30.772 40.112 52.582 1.00 63.96 O Atom 383 N THR A 313 32.473 39.323 51.347 1.00 59.73 N Atom 384 CA THR A 313 32.388 37.989 51.932 1.00 58.55 C Atom 385 CB THR A 313 32.955 36.907 51.000 1.00 57.93 C Atom 386 OG1 THR A 313 34.387 36.975 50.992 1.00 61.30 O Atom 387 CG2 THR A 313 32.425 37.092 49.584 1.00 55.25 C Atom 388 C THR A 313 33.132 37.937 53.262 1.00 56.81 C Atom 389 O THR A 313 33.223 36.885 53.893 1.00 56.45 O Atom 390 N PHE A 314 33.668 39.078 53.683 1.00 57.09 N Atom 391 CA PHE A 314 34.343 39.173 54.972 1.00 56.18 C Atom 392 CB PHE A 314 35.785 39.644 54.797 1.00 59.26 C Atom 393 CG PHE A 314 36.531 39.816 56.092 1.00 61.68 C Atom 394 CD1 PHE A 314 36.908 38.714 56.842 1.00 58.65 C Atom 395 CE1 PHE A 314 37.599 38.866 58.031 1.00 54.45 C Atom 396 CZ PHE A 314 37.929 40.131 58.478 1.00 54.85 C Atom 397 CE2 PHE A 314 37.563 41.235 57.738 1.00 59.88 C Atom 398 CD2 PHE A 314 36.869 41.077 56.551 1.00 61.49 C Atom 399 C PHE A 314 33.576 40.142 55.849 1.00 58.40 C Atom 400 O PHE A 314 33.185 41.216 55.399 1.00 66.31 O Atom 401 N PHE A 315 33.351 39.757 57.100 1.00 60.42 N Atom 402 CA PHE A 315 32.509 40.542 57.992 1.00 60.60 C Atom 403 CB PHE A 315 31.183 39.818 58.251 1.00 59.04 C Atom 404 CG PHE A 315 30.051 40.738 58.618 1.00 65.15 C Atom 405 CD1 PHE A 315 29.554 41.644 57.695 1.00 68.73 C Atom 406 CE1 PHE A 315 28.514 42.492 58.025 1.00 69.14 C Atom 407 CZ PHE A 315 27.953 42.438 59.283 1.00 70.04 C Atom 408 CE2 PHE A 315 28.433 41.535 60.212 1.00 69.11 C Atom 409 CD2 PHE A 315 29.475 40.690 59.878 1.00 65.85 C Atom 410 C PHE A 315 33.223 40.836 59.307 1.00 63.39 C Atom 411 O PHE A 315 32.600 40.867 60.367 1.00 67.11 O Atom 412 N GLY A 316 34.534 41.050 59.230 1.00 58.15 N Atom 413 CA GLY A 316 35.336 41.322 60.409 1.00 59.36 C Atom 414 C GLY A 316 36.209 42.561 60.293 1.00 58.93 C Atom 415 O GLY A 316 37.117 42.764 61.098 1.00 60.49 O Atom 416 N TRP A 317 35.945 43.391 59.290 1.00 57.27 N Atom 417 CA TRP A 317 36.685 44.637 59.129 1.00 58.89 C Atom 418 CB TRP A 317 36.131 45.448 57.954 1.00 56.75 C Atom 419 CG TRP A 317 36.126 44.706 56.656 1.00 60.19 C Atom 420 CD1 TRP A 317 35.038 44.214 55.999 1.00 61.58 C Atom 421 NE1 TRP A 317 35.429 43.592 54.838 1.00 60.20 N Atom 422 CE2 TRP A 317 36.793 43.675 54.726 1.00 61.65 C Atom 423 CD2 TRP A 317 37.265 44.372 55.855 1.00 63.55 C Atom 424 CE3 TRP A 317 38.642 44.592 55.983 1.00 58.40 C Atom 425 CZ3 TRP A 317 39.486 44.116 54.994 1.00 56.88 C Atom 426 CH2 TRP A 317 38.982 43.427 53.882 1.00 57.90 C Atom 427 CZ2 TRP A 317 37.642 43.197 53.731 1.00 59.98 C Atom 428 C TRP A 317 36.618 45.478 60.399 1.00 60.65 C Atom 429 O TRP A 317 35.565 45.584 61.032 1.00 67.13 O Atom 430 N LYS A 318 37.739 46.083 60.770 1.00 57.63 N Atom 431 CA LYS A 318 37.747 46.983 61.914 1.00 61.90 C Atom 432 CB LYS A 318 38.063 46.222 63.199 1.00 59.32 C Atom 433 CG LYS A 318 39.477 45.681 63.284 1.00 61.07 C Atom 434 CD LYS A 318 39.858 45.452 64.742 1.00 70.94 C Atom 435 CE LYS A 318 41.014 44.471 64.895 1.00 66.10 C Atom 436 NZ LYS A 318 41.190 44.074 66.325 1.00 62.93 N Atom 437 C LYS A 318 38.737 48.123 61.726 1.00 62.42 C Atom 438 O LYS A 318 39.444 48.181 60.718 1.00 59.97 O Atom 439 N GLU A 319 38.780 49.025 62.704 1.00 66.43 N Atom 440 CA GLU A 319 39.706 50.155 62.680 1.00 64.32 C Atom 441 CB GLU A 319 39.533 51.023 63.930 1.00 61.29 C Atom 442 CG GLU A 319 40.312 52.329 63.892 1.00 64.44 C Atom 443 CD GLU A 319 39.814 53.271 62.811 1.00 75.35 C Atom 444 OE1 GLU A 319 38.673 53.081 62.338 1.00 81.68 O Atom 445 OE2 GLU A 319 40.559 54.202 62.435 1.00 74.64 O Atom 446 C GLU A 319 41.146 49.666 62.577 1.00 59.62 C Atom 447 O GLU A 319 41.658 49.023 63.494 1.00 54.40 O Atom 448 N PRO A 320 41.804 49.970 61.451 1.00 59.49 N Atom 449 CA PRO A 320 43.168 49.512 61.174 1.00 56.85 C Atom 450 CB PRO A 320 43.454 50.111 59.793 1.00 57.20 C Atom 451 CG PRO A 320 42.523 51.284 59.709 1.00 64.06 C Atom 452 CD PRO A 320 41.272 50.768 60.336 1.00 57.37 C Atom 453 C PRO A 320 44.157 50.058 62.195 1.00 60.52 C Atom 454 O PRO A 320 44.025 51.198 62.642 1.00 64.61 O Atom 455 N ASN A 321 45.143 49.245 62.555 1.00 65.22 N Atom 456 CA ASN A 321 46.138 49.641 63.539 1.00 66.59 C Atom 457 CB ASN A 321 45.628 49.326 64.945 1.00 61.83 C Atom 458 CG ASN A 321 46.745 49.001 65.909 1.00 69.43 C Atom 459 OD1 ASN A 321 46.883 47.860 66.344 1.00 64.68 O Atom 460 ND2 ASN A 321 47.560 49.999 66.239 1.00 76.89 N Atom 461 C ASN A 321 47.488 48.968 63.287 1.00 69.38 C Atom 462 O ASN A 321 47.551 47.790 62.933 1.00 63.73 O Atom 463 N ILE A 322 48.567 49.722 63.470 1.00 68.61 N Atom 464 CA ILE A 322 49.909 49.205 63.239 1.00 64.66 C Atom 465 CB ILE A 322 50.945 50.340 63.182 1.00 64.63 C Atom 466 CG1 ILE A 322 50.575 51.347 62.094 1.00 60.55 C Atom 467 CD1 ILE A 322 51.485 52.546 62.046 1.00 60.98 C Atom 468 CG2 ILE A 322 52.345 49.778 62.953 1.00 66.33 C Atom 469 C ILE A 322 50.316 48.229 64.336 1.00 69.19 C Atom 470 O ILE A 322 50.138 48.508 65.522 1.00 66.41 O Atom 471 N VAL A 323 50.863 47.086 63.928 1.00 66.73 N Atom 472 CA VAL A 323 51.341 46.073 64.864 1.00 65.64 C Atom 473 CB VAL A 323 50.523 44.771 64.765 1.00 64.69 C Atom 474 CG1 VAL A 323 49.143 44.966 65.372 1.00 66.00 C Atom 475 CG2 VAL A 323 50.422 44.314 63.318 1.00 62.04 C Atom 476 C VAL A 323 52.820 45.763 64.646 1.00 65.79 C Atom 477 O VAL A 323 53.519 45.342 65.568 1.00 69.39 O Atom 478 N LYS A 324 53.292 45.969 63.421 1.00 65.09 N Atom 479 CA LYS A 324 54.705 45.793 63.111 1.00 62.25 C Atom 480 CB LYS A 324 54.937 44.447 62.421 1.00 61.18 C Atom 481 CG LYS A 324 56.328 43.862 62.624 1.00 57.68 C Atom 482 CD LYS A 324 57.405 44.718 61.985 1.00 63.13 C Atom 483 CE LYS A 324 57.336 44.666 60.469 1.00 63.49 C Atom 484 NZ LYS A 324 58.440 45.448 59.846 1.00 61.58 N Atom 485 C LYS A 324 55.159 46.935 62.213 1.00 63.54 C Atom 486 O LYS A 324 54.916 46.904 61.006 1.00 63.70 O Atom 487 N PRO A 325 55.821 47.948 62.801 1.00 66.65 N Atom 488 CA PRO A 325 56.225 49.162 62.084 1.00 66.53 C Atom 489 CB PRO A 325 56.701 50.099 63.208 1.00 59.35 C Atom 490 CG PRO A 325 56.278 49.443 64.499 1.00 62.90 C Atom 491 CD PRO A 325 56.260 47.980 64.204 1.00 63.14 C Atom 492 C PRO A 325 57.371 48.912 61.106 1.00 68.09 C Atom 493 O PRO A 325 58.197 48.019 61.316 1.00 61.87 O Atom 494 N HIS A 326 57.401 49.701 60.038 1.00 65.42 N Atom 495 CA HIS A 326 58.505 49.687 59.091 1.00 67.92 C Atom 496 CB HIS A 326 58.019 50.132 57.711 1.00 68.95 C Atom 497 CG HIS A 326 59.071 50.102 56.656 1.00 71.14 C Atom 498 ND1 HIS A 326 60.182 49.278 56.727 1.00 71.06 N Atom 499 CE1 HIS A 326 60.929 49.456 55.661 1.00 70.78 C Atom 500 NE2 HIS A 326 60.348 50.358 54.884 1.00 71.72 N Atom 501 CD2 HIS A 326 59.185 50.769 55.483 1.00 72.16 C Atom 502 C HIS A 326 59.594 50.614 59.619 1.00 75.36 C Atom 503 O HIS A 326 59.442 51.837 59.594 1.00 78.21 O Atom 504 N GLU A 327 60.686 50.027 60.102 1.00 78.90 N Atom 505 CA GLU A 327 61.709 50.779 60.829 1.00 84.25 C Atom 506 CB GLU A 327 62.819 49.856 61.339 1.00 88.12 C Atom 507 CG GLU A 327 62.559 49.294 62.724 1.00 112.49 C Atom 508 CD GLU A 327 63.806 49.270 63.594 1.00 127.96 C Atom 509 OE1 GLU A 327 63.757 49.835 64.710 1.00 136.76 O Atom 510 OE2 GLU A 327 64.834 48.708 63.158 1.00 120.52 O Atom 511 C GLU A 327 62.320 51.961 60.085 1.00 86.38 C Atom 512 O GLU A 327 63.005 52.782 60.689 1.00 93.45 O Atom 513 N LYS A 328 62.072 52.055 58.784 1.00 83.36 N Atom 514 CA LYS A 328 62.632 53.153 58.006 1.00 85.68 C Atom 515 CB LYS A 328 63.549 52.622 56.901 1.00 87.27 C Atom 516 CG LYS A 328 64.695 51.773 57.420 1.00 95.08 C Atom 517 CD LYS A 328 65.922 51.868 56.528 1.00 101.62 C Atom 518 CE LYS A 328 67.096 51.120 57.147 1.00 111.25 C Atom 519 NZ LYS A 328 68.393 51.487 56.511 1.00 121.70 N Atom 520 C LYS A 328 61.566 54.078 57.424 1.00 87.41 C Atom 521 O LYS A 328 61.814 55.265 57.206 1.00 91.38 O Atom 522 N GLY A 329 60.380 53.533 57.180 1.00 82.11 N Atom 523 CA GLY A 329 59.308 54.300 56.574 1.00 77.04 C Atom 524 C GLY A 329 58.532 55.159 57.554 1.00 75.14 C Atom 525 O GLY A 329 58.692 55.040 58.770 1.00 75.56 O Atom 526 N ILE A 330 57.695 56.040 57.016 1.00 73.05 N Atom 527 CA ILE A 330 56.787 56.839 57.826 1.00 77.87 C Atom 528 CB ILE A 330 56.462 58.178 57.143 1.00 81.89 C Atom 529 CG1 ILE A 330 57.750 58.956 56.867 1.00 75.94 C Atom 530 CD1 ILE A 330 57.530 60.269 56.143 1.00 81.39 C Atom 531 CG2 ILE A 330 55.506 58.999 57.998 1.00 81.79 C Atom 532 C ILE A 330 55.502 56.047 58.037 1.00 76.29 C Atom 533 O ILE A 330 54.621 56.035 57.179 1.00 75.07 O Atom 534 N ASN A 331 55.409 55.382 59.182 1.00 75.58 N Atom 535 CA ASN A 331 54.329 54.432 59.443 1.00 75.39 C Atom 536 CB ASN A 331 54.559 53.713 60.774 1.00 71.81 C Atom 537 CG ASN A 331 55.714 52.737 60.711 1.00 73.35 C Atom 538 OD1 ASN A 331 55.579 51.628 60.193 1.00 70.20 O Atom 539 ND2 ASN A 331 56.861 53.145 61.241 1.00 78.51 N Atom 540 C ASN A 331 52.900 54.980 59.360 1.00 76.17 C Atom 541 O ASN A 331 52.041 54.359 58.738 1.00 71.05 O Atom 542 N PRO A 332 52.634 56.132 59.996 1.00 79.92 N Atom 543 CA PRO A 332 51.276 56.678 59.907 1.00 72.21 C Atom 544 CB PRO A 332 51.413 58.055 60.557 1.00 74.54 C Atom 545 CG PRO A 332 52.550 57.901 61.512 1.00 71.06 C Atom 546 CD PRO A 332 53.511 56.957 60.847 1.00 75.13 C Atom 547 C PRO A 332 50.830 56.816 58.454 1.00 70.16 C Atom 548 O PRO A 332 49.634 56.771 58.171 1.00 71.97 O Atom 549 N ASN A 333 51.788 56.978 57.546 1.00 68.26 N Atom 550 CA ASN A 333 51.479 57.101 56.126 1.00 70.33 C Atom 551 CB ASN A 333 52.722 57.499 55.331 1.00 79.42 C Atom 552 CG ASN A 333 52.942 58.998 55.305 1.00 86.19 C Atom 553 OD1 ASN A 333 54.072 59.467 55.161 1.00 82.66 O Atom 554 ND2 ASN A 333 51.860 59.760 55.443 1.00 77.93 N Atom 555 C ASN A 333 50.899 55.817 55.563 1.00 70.97 C Atom 556 O ASN A 333 50.016 55.846 54.705 1.00 73.13 O Atom 557 N TYR A 334 51.406 54.688 56.045 1.00 67.42 N Atom 558 CA TYR A 334 50.898 53.389 55.626 1.00 65.76 C Atom 559 CB TYR A 334 51.781 52.269 56.173 1.00 65.46 C Atom 560 CG TYR A 334 53.187 52.256 55.624 1.00 67.44 C Atom 561 CD1 TYR A 334 53.419 52.028 54.274 1.00 66.87 C Atom 562 CE1 TYR A 334 54.699 52.009 53.762 1.00 72.16 C Atom 563 CZ TYR A 334 55.772 52.214 54.603 1.00 73.79 C Atom 564 OH TYR A 334 57.046 52.192 54.082 1.00 71.32 O Atom 565 CE2 TYR A 334 55.571 52.441 55.953 1.00 68.67 C Atom 566 CD2 TYR A 334 54.282 52.459 56.455 1.00 67.30 C Atom 567 C TYR A 334 49.461 53.200 56.102 1.00 69.92 C Atom 568 O TYR A 334 48.589 52.786 55.338 1.00 66.35 O Atom 569 N LEU A 335 49.226 53.506 57.375 1.00 71.93 N Atom 570 CA LEU A 335 47.899 53.405 57.966 1.00 64.25 C Atom 571 CB LEU A 335 47.940 53.836 59.432 1.00 62.42 C Atom 572 CG LEU A 335 46.673 53.597 60.249 1.00 65.28 C Atom 573 CD1 LEU A 335 46.294 52.136 60.173 1.00 67.94 C Atom 574 CD2 LEU A 335 46.873 54.018 61.694 1.00 65.10 C Atom 575 C LEU A 335 46.892 54.253 57.197 1.00 67.90 C Atom 576 O LEU A 335 45.798 53.791 56.872 1.00 70.23 O Atom 577 N LEU A 336 47.269 55.494 56.904 1.00 65.82 N Atom 578 CA LEU A 336 46.394 56.402 56.167 1.00 71.41 C Atom 579 CB LEU A 336 46.977 57.816 56.140 1.00 75.35 C Atom 580 CG LEU A 336 46.912 58.609 57.447 1.00 73.26 C Atom 581 CD1 LEU A 336 47.571 59.966 57.277 1.00 67.92 C Atom 582 CD2 LEU A 336 45.473 58.761 57.916 1.00 62.81 C Atom 583 C LEU A 336 46.147 55.915 54.743 1.00 67.68 C Atom 584 O LEU A 336 45.049 56.070 54.208 1.00 68.49 O Atom 585 N ALA A 337 47.172 55.329 54.134 1.00 70.76 N Atom 586 CA ALA A 337 47.052 54.800 52.783 1.00 71.70 C Atom 587 CB ALA A 337 48.375 54.201 52.333 1.00 66.78 C Atom 588 C ALA A 337 45.935 53.764 52.711 1.00 70.85 C Atom 589 O ALA A 337 45.128 53.762 51.781 1.00 65.11 O Atom 590 N TRP A 338 45.892 52.886 53.706 1.00 67.05 N Atom 591 CA TRP A 338 44.866 51.856 53.757 1.00 64.22 C Atom 592 CB TRP A 338 45.174 50.835 54.852 1.00 63.47 C Atom 593 CG TRP A 338 44.087 49.821 55.038 1.00 65.45 C Atom 594 CD1 TRP A 338 43.415 49.542 56.192 1.00 61.16 C Atom 595 NE1 TRP A 338 42.486 48.556 55.971 1.00 63.59 N Atom 596 CE2 TRP A 338 42.538 48.184 54.649 1.00 61.98 C Atom 597 CD2 TRP A 338 43.533 48.965 54.034 1.00 62.98 C Atom 598 CE3 TRP A 338 43.786 48.776 52.670 1.00 60.31 C Atom 599 CZ3 TRP A 338 43.049 47.832 51.981 1.00 59.56 C Atom 600 CH2 TRP A 338 42.065 47.072 52.626 1.00 61.47 C Atom 601 CZ2 TRP A 338 41.795 47.233 53.957 1.00 60.19 C Atom 602 C TRP A 338 43.486 52.467 53.977 1.00 66.00 C Atom 603 O TRP A 338 42.531 52.133 53.277 1.00 65.97 O Atom 604 N LYS A 339 43.387 53.369 54.946 1.00 65.93 N Atom 605 CA LYS A 339 42.119 54.035 55.219 1.00 68.94 C Atom 606 CB LYS A 339 42.263 55.028 56.371 1.00 67.16 C Atom 607 CG LYS A 339 42.345 54.378 57.741 1.00 67.13 C Atom 608 CD LYS A 339 42.286 55.433 58.835 1.00 75.62 C Atom 609 CE LYS A 339 42.698 54.858 60.181 1.00 78.54 C Atom 610 NZ LYS A 339 42.982 55.925 61.184 1.00 84.99 N Atom 611 C LYS A 339 41.589 54.735 53.973 1.00 67.94 C Atom 612 O LYS A 339 40.396 54.675 53.677 1.00 71.15 O Atom 613 N GLN A 340 42.483 55.394 53.244 1.00 65.33 N Atom 614 CA GLN A 340 42.112 56.042 51.994 1.00 68.67 C Atom 615 CB GLN A 340 43.311 56.773 51.392 1.00 71.11 C Atom 616 CG GLN A 340 43.035 57.366 50.024 1.00 74.83 C Atom 617 CD GLN A 340 44.159 58.252 49.532 1.00 76.69 C Atom 618 OE1 GLN A 340 45.071 58.598 50.285 1.00 76.71 O Atom 619 NE2 GLN A 340 44.097 58.630 48.262 1.00 80.28 N Atom 620 C GLN A 340 41.568 55.020 51.002 1.00 71.36 C Atom 621 O GLN A 340 40.645 55.310 50.243 1.00 71.81 O Atom 622 N VAL A 341 42.143 53.822 51.017 1.00 72.45 N Atom 623 CA VAL A 341 41.675 52.748 50.154 1.00 71.84 C Atom 624 CB VAL A 341 42.567 51.495 50.267 1.00 72.69 C Atom 625 CG1 VAL A 341 41.917 50.314 49.563 1.00 67.21 C Atom 626 CG2 VAL A 341 43.949 51.773 49.693 1.00 66.64 C Atom 627 C VAL A 341 40.236 52.383 50.493 1.00 71.68 C Atom 628 O VAL A 341 39.385 52.298 49.608 1.00 76.28 O Atom 629 N LEU A 342 39.969 52.172 51.779 1.00 71.75 N Atom 630 CA LEU A 342 38.620 51.852 52.236 1.00 70.14 C Atom 631 CB LEU A 342 38.591 51.642 53.751 1.00 62.97 C Atom 632 CG LEU A 342 39.316 50.417 54.305 1.00 66.34 C Atom 633 CD1 LEU A 342 39.180 50.361 55.819 1.00 63.20 C Atom 634 CD2 LEU A 342 38.788 49.145 53.663 1.00 60.44 C Atom 635 C LEU A 342 37.658 52.967 51.862 1.00 73.97 C Atom 636 O LEU A 342 36.586 52.721 51.312 1.00 75.78 O Atom 637 N ALA A 343 38.055 54.197 52.170 1.00 74.68 N Atom 638 CA ALA A 343 37.231 55.365 51.898 1.00 73.37 C Atom 639 CB ALA A 343 37.971 56.628 52.286 1.00 67.53 C Atom 640 C ALA A 343 36.804 55.421 50.435 1.00 77.32 C Atom 641 O ALA A 343 35.617 55.536 50.129 1.00 80.74 O Atom 642 N GLU A 344 37.775 55.331 49.533 1.00 73.48 N Atom 643 CA GLU A 344 37.492 55.419 48.106 1.00 81.86 C Atom 644 CB GLU A 344 38.778 55.669 47.312 1.00 79.92 C Atom 645 CG GLU A 344 39.444 56.998 47.658 1.00 86.11 C Atom 646 CD GLU A 344 40.512 57.404 46.660 1.00 91.79 C Atom 647 OE1 GLU A 344 40.411 57.000 45.483 1.00 95.46 O Atom 648 OE2 GLU A 344 41.447 58.135 47.051 1.00 86.57 O Atom 649 C GLU A 344 36.752 54.183 47.595 1.00 81.70 C Atom 650 O GLU A 344 36.052 54.244 46.585 1.00 86.75 O Atom 651 N LEU A 345 36.899 53.065 48.300 1.00 83.05 N Atom 652 CA LEU A 345 36.147 51.859 47.971 1.00 79.69 C Atom 653 CB LEU A 345 36.700 50.646 48.723 1.00 77.48 C Atom 654 CG LEU A 345 37.889 49.925 48.081 1.00 79.66 C Atom 655 CD1 LEU A 345 38.555 48.992 49.079 1.00 78.96 C Atom 656 CD2 LEU A 345 37.460 49.160 46.832 1.00 73.98 C Atom 657 C LEU A 345 34.664 52.055 48.277 1.00 82.17 C Atom 658 O LEU A 345 33.800 51.538 47.570 1.00 81.88 O Atom 659 N GLN A 346 34.377 52.811 49.332 1.00 81.52 N Atom 660 CA GLN A 346 33.002 53.149 49.679 1.00 85.32 C Atom 661 CB GLN A 346 32.945 53.844 51.039 1.00 86.41 C Atom 662 CG GLN A 346 32.820 52.895 52.214 1.00 86.24 C Atom 663 CD GLN A 346 33.223 53.541 53.523 1.00 92.31 C Atom 664 OE1 GLN A 346 34.222 54.258 53.593 1.00 95.22 O Atom 665 NE2 GLN A 346 32.451 53.286 54.572 1.00 93.03 N Atom 666 C GLN A 346 32.372 54.035 48.611 1.00 90.94 C Atom 667 O GLN A 346 31.194 53.891 48.292 1.00 95.87 O Atom 668 N ASP A 347 33.162 54.952 48.063 1.00 88.88 N Atom 669 CA ASP A 347 32.686 55.829 47.000 1.00 91.00 C Atom 670 CB ASP A 347 33.823 56.709 46.479 1.00 95.55 C Atom 671 CG ASP A 347 34.259 57.756 47.485 1.00 98.95 C Atom 672 OD1 ASP A 347 33.521 57.978 48.470 1.00 100.39 O Atom 673 OD2 ASP A 347 35.336 58.360 47.286 1.00 97.77 O Atom 674 C ASP A 347 32.092 55.026 45.852 1.00 97.70 C Atom 675 O ASP A 347 31.047 55.381 45.310 1.00 108.08 O Atom 676 N ILE A 348 32.763 53.938 45.488 1.00 93.97 N Atom 677 CA ILE A 348 32.333 53.119 44.362 1.00 101.99 C Atom 678 CB ILE A 348 33.473 52.225 43.848 1.00 101.00 C Atom 679 CG1 ILE A 348 34.821 52.719 44.370 1.00 100.24 C Atom 680 CD1 ILE A 348 35.944 51.718 44.193 1.00 101.51 C Atom 681 CG2 ILE A 348 33.459 52.172 42.330 1.00 109.28 C Atom 682 C ILE A 348 31.156 52.222 44.727 1.00 110.28 C Atom 683 O ILE A 348 30.308 51.926 43.885 1.00 114.34 O Atom 684 N GLU A 349 31.117 51.783 45.982 1.00 108.28 N Atom 685 CA GLU A 349 30.064 50.887 46.446 1.00 108.25 C Atom 686 CB GLU A 349 30.048 50.800 47.973 1.00 103.90 C Atom 687 CG GLU A 349 29.086 49.755 48.505 1.00 101.97 C Atom 688 CD GLU A 349 28.731 49.963 49.963 1.00 98.68 C Atom 689 OE1 GLU A 349 29.107 51.009 50.535 1.00 94.99 O Atom 690 OE2 GLU A 349 28.065 49.077 50.535 1.00 92.47 O Atom 691 C GLU A 349 28.703 51.343 45.931 1.00 122.22 C Atom 692 O GLU A 349 28.349 52.519 46.040 1.00 116.36 O Atom 693 N ASN A 350 27.950 50.401 45.370 1.00 126.66 N Atom 694 CA ASN A 350 26.687 50.703 44.703 1.00 123.73 C Atom 695 CB ASN A 350 25.731 51.464 45.625 1.00 125.50 C Atom 696 CG ASN A 350 24.744 50.548 46.327 1.00 129.38 C Atom 697 OD1 ASN A 350 24.808 49.325 46.192 1.00 119.48 O Atom 698 ND2 ASN A 350 23.820 51.140 47.078 1.00 123.78 N Atom 699 C ASN A 350 26.878 51.449 43.386 1.00 126.05 C Atom 700 O ASN A 350 27.284 50.855 42.388 1.00 127.58 O Atom 701 N GLU A 351 26.593 52.749 43.385 1.00 128.53 N Atom 702 CA GLU A 351 26.597 53.512 42.143 1.00 134.66 C Atom 703 CB GLU A 351 28.029 53.738 41.652 1.00 129.91 C Atom 704 CG GLU A 351 28.507 55.184 41.718 1.00 130.54 C Atom 705 CD GLU A 351 28.584 55.737 43.132 1.00 126.54 C Atom 706 OE1 GLU A 351 28.078 55.083 44.070 1.00 126.25 O Atom 707 OE2 GLU A 351 29.154 56.837 43.300 1.00 119.67 O Atom 708 C GLU A 351 25.795 52.753 41.093 1.00 140.20 C Atom 709 O GLU A 351 24.664 52.334 41.344 1.00 144.17 O Atom 710 N GLU A 352 26.387 52.575 39.919 1.00 135.51 N Atom 711 CA GLU A 352 25.811 51.716 38.892 1.00 138.12 C Atom 712 CB GLU A 352 24.927 52.509 37.928 1.00 145.30 C Atom 713 CG GLU A 352 23.471 52.620 38.354 1.00 145.11 C Atom 714 CD GLU A 352 23.161 53.921 39.068 1.00 150.85 C Atom 715 OE1 GLU A 352 24.099 54.559 39.593 1.00 148.34 O Atom 716 OE2 GLU A 352 21.973 54.306 39.095 1.00 151.17 O Atom 717 C GLU A 352 26.925 51.018 38.125 1.00 134.80 C Atom 718 O GLU A 352 27.083 49.799 38.208 1.00 134.03 O Atom 719 N LYS A 353 27.701 51.800 37.383 1.00 134.65 N Atom 720 CA LYS A 353 28.820 51.256 36.626 1.00 143.81 C Atom 721 CB LYS A 353 28.873 51.859 35.218 1.00 148.43 C Atom 722 CG LYS A 353 27.607 51.629 34.404 1.00 143.87 C Atom 723 CD LYS A 353 27.905 51.475 32.918 1.00 149.09 C Atom 724 CE LYS A 353 28.415 52.768 32.301 1.00 150.83 C Atom 725 NZ LYS A 353 28.725 52.589 30.853 1.00 141.33 N Atom 726 C LYS A 353 30.142 51.466 37.358 1.00 137.46 C Atom 727 O LYS A 353 30.705 52.561 37.348 1.00 124.43 O Atom 728 N ILE A 354 30.623 50.406 38.001 1.00 131.78 N Atom 729 CA ILE A 354 31.920 50.434 38.665 1.00 123.01 C Atom 730 CB ILE A 354 32.081 49.265 39.659 1.00 114.97 C Atom 731 CG1 ILE A 354 31.433 49.605 41.005 1.00 113.64 C Atom 732 CD1 ILE A 354 29.923 49.524 41.008 1.00 120.78 C Atom 733 CG2 ILE A 354 33.552 48.931 39.860 1.00 110.56 C Atom 734 C ILE A 354 33.039 50.373 37.631 1.00 121.42 C Atom 735 O ILE A 354 33.079 49.460 36.805 1.00 120.88 O Atom 736 N PRO A 355 33.952 51.353 37.673 1.00 118.07 N Atom 737 CA PRO A 355 35.060 51.469 36.719 1.00 115.23 C Atom 738 CB PRO A 355 35.683 52.818 37.093 1.00 113.49 C Atom 739 CG PRO A 355 35.338 52.978 38.541 1.00 110.06 C Atom 740 CD PRO A 355 33.928 52.490 38.606 1.00 113.30 C Atom 741 C PRO A 355 36.107 50.376 36.899 1.00 120.59 C Atom 742 O PRO A 355 36.190 49.758 37.962 1.00 117.71 O Atom 743 N LYS A 356 36.898 50.143 35.858 1.00 123.58 N Atom 744 CA LYS A 356 38.095 49.329 35.990 1.00 121.36 C Atom 745 CB LYS A 356 38.673 48.971 34.616 1.00 124.32 C Atom 746 CG LYS A 356 38.057 47.746 33.949 1.00 122.58 C Atom 747 CD LYS A 356 38.599 47.561 32.532 1.00 129.23 C Atom 748 CE LYS A 356 40.066 47.141 32.525 1.00 129.83 C Atom 749 NZ LYS A 356 40.233 45.660 32.620 1.00 122.70 N Atom 750 C LYS A 356 39.125 50.115 36.796 1.00 123.03 C Atom 751 O LYS A 356 39.215 51.338 36.678 1.00 115.29 O Atom 752 N THR A 357 39.885 49.402 37.621 1.00 113.45 N Atom 753 CA THR A 357 41.021 49.959 38.370 1.00 106.63 C Atom 754 CB THR A 357 42.265 50.176 37.465 1.00 107.20 C Atom 755 OG1 THR A 357 43.401 50.486 38.280 1.00 106.43 O Atom 756 CG2 THR A 357 42.038 51.298 36.454 1.00 111.78 C Atom 757 C THR A 357 40.753 51.196 39.262 1.00 105.55 C Atom 758 O THR A 357 40.940 51.124 40.474 1.00 103.16 O Atom 759 N LYS A 358 40.342 52.317 38.669 1.00 100.02 N Atom 760 CA LYS A 358 40.040 53.548 39.416 1.00 96.81 C Atom 761 CB LYS A 358 39.191 53.258 40.657 1.00 96.86 C Atom 762 CG LYS A 358 38.923 54.484 41.526 1.00 96.47 C Atom 763 CD LYS A 358 37.962 54.159 42.663 1.00 95.55 C Atom 764 CE LYS A 358 37.304 55.415 43.219 1.00 91.78 C Atom 765 NZ LYS A 358 38.283 56.324 43.861 1.00 89.06 N Atom 766 C LYS A 358 41.272 54.356 39.822 1.00 95.71 C Atom 767 O LYS A 358 42.285 53.801 40.246 1.00 96.71 O Atom 768 N ASN A 359 41.163 55.677 39.702 1.00 99.64 N Atom 769 CA ASN A 359 42.245 56.586 40.066 1.00 96.22 C Atom 770 CB ASN A 359 42.328 57.750 39.075 1.00 102.21 C Atom 771 CG ASN A 359 41.751 57.406 37.712 1.00 111.96 C Atom 772 OD1 ASN A 359 42.469 57.380 36.713 1.00 110.79 O Atom 773 ND2 ASN A 359 40.445 57.144 37.666 1.00 109.12 N Atom 774 C ASN A 359 42.053 57.136 41.476 1.00 87.81 C Atom 775 O ASN A 359 40.938 57.486 41.862 1.00 89.68 O Atom 776 N MET A 360 43.139 57.227 42.236 1.00 86.57 N Atom 777 CA MET A 360 43.053 57.654 43.627 1.00 85.93 C Atom 778 CB MET A 360 43.860 56.721 44.533 1.00 88.04 C Atom 779 CG MET A 360 43.341 55.295 44.577 1.00 83.50 C Atom 780 SD MET A 360 44.052 54.351 45.938 1.00 88.13 S Atom 781 CE MET A 360 43.281 55.145 47.344 1.00 76.71 C Atom 782 C MET A 360 43.492 59.096 43.848 1.00 85.69 C Atom 783 O MET A 360 44.227 59.672 43.045 1.00 84.91 O Atom 784 N ARG A 361 43.033 59.662 44.958 1.00 87.50 N Atom 785 CA ARG A 361 43.345 61.033 45.332 1.00 88.48 C Atom 786 CB ARG A 361 42.456 61.448 46.506 1.00 92.56 C Atom 787 CG ARG A 361 42.424 62.933 46.810 1.00 99.28 C Atom 788 CD ARG A 361 41.231 63.264 47.695 1.00 108.29 C Atom 789 NE ARG A 361 41.384 64.544 48.380 1.00 120.83 N Atom 790 CZ ARG A 361 41.883 64.682 49.604 1.00 122.28 C Atom 791 NH1 ARG A 361 42.278 63.615 50.286 1.00 113.20 N Atom 792 NH2 ARG A 361 41.985 65.887 50.147 1.00 125.44 N Atom 793 C ARG A 361 44.820 61.153 45.706 1.00 84.62 C Atom 794 O ARG A 361 45.303 60.445 46.589 1.00 83.95 O Atom 795 N LYS A 362 45.536 62.045 45.028 1.00 84.36 N Atom 796 CA LYS A 362 46.966 62.212 45.267 1.00 87.05 C Atom 797 CB LYS A 362 47.616 62.995 44.124 1.00 85.87 C Atom 798 CG LYS A 362 47.288 62.448 42.744 1.00 85.22 C Atom 799 CD LYS A 362 48.396 62.753 41.751 1.00 88.28 C Atom 800 CE LYS A 362 48.048 62.238 40.363 1.00 99.03 C Atom 801 NZ LYS A 362 46.950 63.035 39.740 1.00 109.31 N Atom 802 C LYS A 362 47.239 62.885 46.611 1.00 84.90 C Atom 803 O LYS A 362 47.656 64.040 46.670 1.00 84.95 O Atom 804 N THR A 363 47.007 62.142 47.689 1.00 83.06 N Atom 805 CA THR A 363 47.139 62.669 49.041 1.00 78.01 C Atom 806 CB THR A 363 46.300 61.848 50.035 1.00 82.25 C Atom 807 OG1 THR A 363 46.872 60.543 50.180 1.00 82.74 O Atom 808 CG2 THR A 363 44.871 61.716 49.539 1.00 83.53 C Atom 809 C THR A 363 48.584 62.681 49.525 1.00 79.18 C Atom 810 O THR A 363 49.488 62.207 48.839 1.00 80.58 O Atom 811 N SER A 364 48.787 63.223 50.719 1.00 80.66 N Atom 812 CA SER A 364 50.108 63.280 51.325 1.00 76.51 C Atom 813 CB SER A 364 50.020 63.936 52.703 1.00 74.83 C Atom 814 OG SER A 364 51.171 63.655 53.479 1.00 93.98 O Atom 815 C SER A 364 50.746 61.897 51.446 1.00 84.19 C Atom 816 O SER A 364 51.908 61.703 51.083 1.00 82.15 O Atom 817 N GLN A 365 49.979 60.939 51.957 1.00 82.05 N Atom 818 CA GLN A 365 50.497 59.599 52.218 1.00 82.99 C Atom 819 CB GLN A 365 49.455 58.754 52.953 1.00 79.55 C Atom 820 CG GLN A 365 48.552 59.552 53.877 1.00 83.15 C Atom 821 CD GLN A 365 47.308 60.066 53.178 1.00 80.19 C Atom 822 OE1 GLN A 365 46.565 59.299 52.566 1.00 76.09 O Atom 823 NE2 GLN A 365 47.069 61.369 53.274 1.00 84.96 N Atom 824 C GLN A 365 50.911 58.897 50.929 1.00 80.16 C Atom 825 O GLN A 365 51.980 58.290 50.859 1.00 71.14 O Atom 826 N LEU A 366 50.058 58.979 49.912 1.00 79.32 N Atom 827 CA LEU A 366 50.336 58.325 48.639 1.00 77.71 C Atom 828 CB LEU A 366 49.095 58.309 47.746 1.00 80.89 C Atom 829 CG LEU A 366 47.941 57.449 48.255 1.00 78.19 C Atom 830 CD1 LEU A 366 46.884 57.273 47.175 1.00 74.78 C Atom 831 CD2 LEU A 366 48.465 56.101 48.719 1.00 76.11 C Atom 832 C LEU A 366 51.507 58.976 47.915 1.00 82.22 C Atom 833 O LEU A 366 52.357 58.283 47.355 1.00 87.68 O Atom 834 N LYS A 367 51.550 60.305 47.923 1.00 84.57 N Atom 835 CA LYS A 367 52.679 61.026 47.347 1.00 83.70 C Atom 836 CB LYS A 367 52.543 62.532 47.572 1.00 83.28 C Atom 837 CG LYS A 367 51.544 63.222 46.661 1.00 90.40 C Atom 838 CD LYS A 367 51.670 64.735 46.770 1.00 98.44 C Atom 839 CE LYS A 367 50.597 65.442 45.955 1.00 109.33 C Atom 840 NZ LYS A 367 50.752 66.923 46.022 1.00 121.11 N Atom 841 C LYS A 367 53.982 60.529 47.961 1.00 80.64 C Atom 842 O LYS A 367 54.938 60.230 47.251 1.00 86.53 O Atom 843 N TRP A 368 54.008 60.434 49.286 1.00 74.56 N Atom 844 CA TRP A 368 55.203 60.001 49.998 1.00 74.58 C Atom 845 CB TRP A 368 55.005 60.118 51.510 1.00 71.73 C Atom 846 CG TRP A 368 56.114 59.484 52.282 1.00 75.43 C Atom 847 CD1 TRP A 368 57.311 60.048 52.610 1.00 79.27 C Atom 848 NE1 TRP A 368 58.080 59.153 53.313 1.00 85.07 N Atom 849 CE2 TRP A 368 57.382 57.982 53.451 1.00 86.44 C Atom 850 CD2 TRP A 368 56.139 58.153 52.810 1.00 83.44 C Atom 851 CE3 TRP A 368 55.229 57.092 52.807 1.00 79.80 C Atom 852 CZ3 TRP A 368 55.586 55.912 53.432 1.00 79.09 C Atom 853 CH2 TRP A 368 56.830 55.771 54.061 1.00 75.04 C Atom 854 CZ2 TRP A 368 57.739 56.791 54.081 1.00 76.65 C Atom 855 C TRP A 368 55.603 58.573 49.640 1.00 82.30 C Atom 856 O TRP A 368 56.716 58.327 49.177 1.00 89.34 O Atom 857 N ALA A 369 54.691 57.634 49.864 1.00 84.85 N Atom 858 CA ALA A 369 54.969 56.220 49.633 1.00 81.63 C Atom 859 CB ALA A 369 53.753 55.373 49.992 1.00 75.76 C Atom 860 C ALA A 369 55.400 55.954 48.195 1.00 83.05 C Atom 861 O ALA A 369 56.287 55.136 47.943 1.00 79.33 O Atom 862 N LEU A 370 54.772 56.655 47.258 1.00 80.61 N Atom 863 CA LEU A 370 55.065 56.476 45.842 1.00 84.86 C Atom 864 CB LEU A 370 53.830 56.797 45.000 1.00 84.58 C Atom 865 CG LEU A 370 52.632 55.883 45.270 1.00 87.55 C Atom 866 CD1 LEU A 370 51.361 56.437 44.644 1.00 80.91 C Atom 867 CD2 LEU A 370 52.909 54.471 44.773 1.00 80.59 C Atom 868 C LEU A 370 56.263 57.315 45.394 1.00 94.08 C Atom 869 O LEU A 370 56.464 57.534 44.199 1.00 95.78 O Atom 870 N GLY A 371 57.057 57.770 46.362 1.00 91.39 N Atom 871 CA GLY A 371 58.258 58.542 46.091 1.00 96.47 C Atom 872 C GLY A 371 58.026 59.751 45.205 1.00 108.32 C Atom 873 O GLY A 371 58.719 59.936 44.205 1.00 111.98 O Atom 874 N GLU A 372 57.056 60.580 45.574 1.00 103.88 N Atom 875 CA GLU A 372 56.700 61.738 44.762 1.00 108.20 C Atom 876 CB GLU A 372 55.186 61.946 44.744 1.00 107.60 C Atom 877 CG GLU A 372 54.685 62.523 43.436 1.00 116.88 C Atom 878 CD GLU A 372 55.128 61.693 42.244 1.00 126.53 C Atom 879 OE1 GLU A 372 55.583 62.288 41.243 1.00 133.58 O Atom 880 OE2 GLU A 372 55.037 60.446 42.317 1.00 117.29 O Atom 881 C GLU A 372 57.409 63.011 45.222 1.00 121.07 C Atom 882 O GLU A 372 57.570 63.954 44.448 1.00 122.33 O Atom 883 N ASN A 373 57.819 63.042 46.486 1.00 121.99 N Atom 884 CA ASN A 373 58.655 64.133 46.973 1.00 123.48 C Atom 885 CB ASN A 373 58.653 64.201 48.504 1.00 122.94 C Atom 886 CG ASN A 373 58.270 62.879 49.150 1.00 120.74 C Atom 887 OD1 ASN A 373 57.432 62.842 50.053 1.00 110.60 O Atom 888 ND2 ASN A 373 58.872 61.788 48.684 1.00 112.32 N Atom 889 C ASN A 373 60.071 64.007 46.422 1.00 123.04 C Atom 890 O ASN A 373 60.843 64.966 46.427 1.00 129.13 O Atom 891 N MET A 374 60.397 62.813 45.936 1.00 122.62 N Atom 892 CA MET A 374 61.654 62.588 45.237 1.00 127.39 C Atom 893 CB MET A 374 62.011 61.100 45.225 1.00 130.41 C Atom 894 CG MET A 374 62.720 60.603 46.475 1.00 130.98 C Atom 895 SD MET A 374 63.219 58.875 46.327 1.00 156.03 S Atom 896 CE MET A 374 64.209 58.923 44.833 1.00 136.86 C Atom 897 C MET A 374 61.560 63.105 43.807 1.00 132.76 C Atom 898 O MET A 374 62.519 63.010 43.042 1.00 131.77 O Atom 899 N ALA A 375 60.396 63.644 43.451 1.00 131.64 N Atom 900 CA ALA A 375 60.186 64.197 42.117 1.00 133.74 C Atom 901 CB ALA A 375 58.770 64.727 41.967 1.00 133.16 C Atom 902 C ALA A 375 61.201 65.295 41.827 1.00 142.41 C Atom 903 O ALA A 375 61.350 66.235 42.610 1.00 140.63 O Atom 904 N PRO A 376 61.902 65.170 40.692 1.00 145.20 N Atom 905 CA PRO A 376 63.001 66.033 40.241 1.00 136.34 C Atom 906 CB PRO A 376 63.158 65.645 38.772 1.00 131.86 C Atom 907 CG PRO A 376 62.707 64.229 38.724 1.00 130.32 C Atom 908 CD PRO A 376 61.607 64.100 39.723 1.00 140.10 C Atom 909 C PRO A 376 62.710 67.528 40.358 1.00 135.20 C Atom 910 O PRO A 376 63.649 68.313 40.480 1.00 128.26 O Atom 911 N GLU A 377 61.439 67.916 40.322 1.00 138.80 N Atom 912 CA GLU A 377 61.091 69.332 40.381 1.00 138.15 C Atom 913 CB GLU A 377 59.580 69.544 40.239 1.00 146.77 C Atom 914 CG GLU A 377 58.985 69.095 38.914 1.00 149.87 C Atom 915 CD GLU A 377 58.030 67.924 39.067 1.00 153.48 C Atom 916 OE1 GLU A 377 57.423 67.785 40.151 1.00 150.37 O Atom 917 OE2 GLU A 377 57.879 67.149 38.098 1.00 150.03 O Atom 918 C GLU A 377 61.580 70.006 41.661 1.00 145.61 C Atom 919 O GLU A 377 61.686 71.231 41.720 1.00 147.92 O Atom 920 N LYS A 378 61.883 69.208 42.681 1.00 148.44 N Atom 921 CA LYS A 378 62.187 69.753 44.003 1.00 154.06 C Atom 922 CB LYS A 378 61.211 69.192 45.043 1.00 151.58 C Atom 923 CG LYS A 378 59.760 69.582 44.797 1.00 151.87 C Atom 924 CD LYS A 378 58.830 68.954 45.823 1.00 146.49 C Atom 925 CE LYS A 378 58.789 67.443 45.674 1.00 138.21 C Atom 926 NZ LYS A 378 58.275 67.034 44.337 1.00 136.10 N Atom 927 C LYS A 378 63.631 69.547 44.473 1.00 151.27 C Atom 928 O LYS A 378 64.112 68.416 44.541 1.00 142.61 O Atom 929 N VAL A 379 64.293 70.663 44.787 1.00 154.34 N Atom 930 CA VAL A 379 65.622 70.713 45.418 1.00 149.13 C Atom 931 CB VAL A 379 66.338 69.344 45.468 1.00 148.75 C Atom 932 CG1 VAL A 379 67.118 69.098 44.190 1.00 150.57 C Atom 933 CG2 VAL A 379 67.254 69.268 46.686 1.00 153.14 C Atom 934 C VAL A 379 66.512 71.766 44.748 1.00 151.00 C Atom 935 O VAL A 379 66.095 72.417 43.790 1.00 151.82 O Atom 936 N ASP A 380 67.731 71.935 45.256 1.00 152.20 N Atom 937 CA ASP A 380 68.606 73.014 44.801 1.00 152.72 C Atom 938 CB ASP A 380 68.731 74.079 45.893 1.00 151.20 C Atom 939 CG ASP A 380 67.429 74.814 46.141 1.00 151.80 C Atom 940 OD1 ASP A 380 67.040 75.637 45.286 1.00 148.67 O Atom 941 OD2 ASP A 380 66.801 74.577 47.195 1.00 150.66 O Atom 942 C ASP A 380 70.001 72.551 44.381 1.00 148.41 C Atom 943 O ASP A 380 70.150 71.587 43.630 1.00 140.84 O Atom 944 N PHE A 381 71.016 73.264 44.867 1.00 148.15 N Atom 945 CA PHE A 381 72.416 72.945 44.594 1.00 145.69 C Atom 946 CB PHE A 381 73.338 73.901 45.361 1.00 144.53 C Atom 947 CG PHE A 381 74.659 74.156 44.682 1.00 150.10 C Atom 948 CD1 PHE A 381 74.938 75.394 44.122 1.00 148.21 C Atom 949 CE1 PHE A 381 76.149 75.632 43.498 1.00 146.05 C Atom 950 CZ PHE A 381 77.095 74.632 43.429 1.00 150.54 C Atom 951 CE2 PHE A 381 76.831 73.396 43.982 1.00 145.87 C Atom 952 CD2 PHE A 381 75.620 73.163 44.605 1.00 147.23 C Atom 953 C PHE A 381 72.701 71.506 45.003 1.00 147.26 C Atom 954 O PHE A 381 73.702 70.914 44.597 1.00 148.23 O Atom 955 N GLU A 382 71.807 70.954 45.815 1.00 150.93 N Atom 956 CA GLU A 382 71.904 69.570 46.253 1.00 154.83 C Atom 957 CB GLU A 382 70.884 69.305 47.365 1.00 156.09 C Atom 958 CG GLU A 382 71.234 68.146 48.285 1.00 159.12 C Atom 959 CD GLU A 382 70.460 66.883 47.964 1.00 155.82 C Atom 960 OE1 GLU A 382 71.095 65.869 47.607 1.00 155.10 O Atom 961 OE2 GLU A 382 69.215 66.906 48.069 1.00 154.20 O Atom 962 C GLU A 382 71.670 68.644 45.062 1.00 152.82 C Atom 963 O GLU A 382 71.726 67.421 45.184 1.00 151.25 O Atom 964 N ASP A 383 71.415 69.247 43.905 1.00 149.55 N Atom 965 CA ASP A 383 71.196 68.507 42.670 1.00 146.43 C Atom 966 CB ASP A 383 70.415 69.373 41.681 1.00 135.21 C Atom 967 CG ASP A 383 69.695 68.558 40.629 1.00 133.11 C Atom 968 OD1 ASP A 383 70.121 67.417 40.356 1.00 137.12 O Atom 969 OD2 ASP A 383 68.702 69.066 40.070 1.00 126.06 O Atom 970 C ASP A 383 72.534 68.093 42.063 1.00 145.80 C Atom 971 O ASP A 383 72.696 68.076 40.842 1.00 135.99 O Atom 972 N CYS A 384 73.490 67.769 42.930 1.00 149.74 N Atom 973 CA CYS A 384 74.832 67.388 42.502 1.00 146.31 C Atom 974 CB CYS A 384 75.744 68.616 42.455 1.00 139.53 C Atom 975 SG CYS A 384 75.045 70.036 41.584 1.00 134.66 S Atom 976 C CYS A 384 75.433 66.339 43.436 1.00 143.87 C Atom 977 O CYS A 384 76.566 66.483 43.898 1.00 138.09 O Atom 978 N LYS A 385 74.668 65.286 43.711 1.00 149.14 N Atom 979 CA LYS A 385 75.116 64.215 44.599 1.00 154.49 C Atom 980 CB LYS A 385 73.984 63.777 45.540 1.00 150.61 C Atom 981 CG LYS A 385 72.787 63.133 44.847 1.00 144.06 C Atom 982 CD LYS A 385 72.027 64.131 43.991 1.00 142.52 C Atom 983 CE LYS A 385 71.380 63.446 42.798 1.00 143.69 C Atom 984 NZ LYS A 385 70.566 62.264 43.198 1.00 143.49 N Atom 985 C LYS A 385 75.657 63.025 43.805 1.00 153.61 C Atom 986 O LYS A 385 74.897 62.201 43.297 1.00 151.42 O Atom 987 N ASP A 386 76.980 62.941 43.702 1.00 151.38 N Atom 988 CA ASP A 386 77.613 61.916 42.881 1.00 147.90 C Atom 989 CB ASP A 386 78.142 62.534 41.585 1.00 141.29 C Atom 990 CG ASP A 386 77.524 63.889 41.288 1.00 136.26 C Atom 991 OD1 ASP A 386 76.749 63.994 40.314 1.00 126.10 O Atom 992 OD2 ASP A 386 77.812 64.850 42.032 1.00 137.26 O Atom 993 C ASP A 386 78.755 61.234 43.627 1.00 152.94 C Atom 994 O ASP A 386 79.869 61.754 43.677 1.00 158.53 O Atom 995 N VAL A 387 78.477 60.067 44.201 1.00 154.31 N Atom 996 CA VAL A 387 79.482 59.341 44.970 1.00 161.69 C Atom 997 CB VAL A 387 78.848 58.223 45.831 1.00 162.05 C Atom 998 CG1 VAL A 387 79.884 57.625 46.775 1.00 150.79 C Atom 999 CG2 VAL A 387 77.662 58.762 46.618 1.00 159.92 C Atom 1000 C VAL A 387 80.562 58.746 44.066 1.00 164.18 C Atom 1001 O VAL A 387 81.465 59.453 43.614 1.00 153.43 O Atom 1002 N SER A 388 80.459 57.447 43.804 1.00 166.98 N Atom 1003 CA SER A 388 81.447 56.744 42.993 1.00 163.92 C Atom 1004 CB SER A 388 81.432 55.246 43.311 1.00 162.13 C Atom 1005 OG SER A 388 80.164 54.676 43.034 1.00 161.75 O Atom 1006 C SER A 388 81.199 56.970 41.505 1.00 158.97 C Atom 1007 O SER A 388 82.128 56.923 40.698 1.00 152.99 O Atom 1008 N GLU A 397 80.349 46.159 49.850 1.00 138.48 N Atom 1009 CA GLU A 397 79.540 46.200 51.063 1.00 134.17 C Atom 1010 CB GLU A 397 80.082 47.254 52.032 1.00 135.08 C Atom 1011 CG GLU A 397 80.528 48.545 51.364 1.00 145.09 C Atom 1012 CD GLU A 397 81.178 49.510 52.339 1.00 148.85 C Atom 1013 OE1 GLU A 397 80.993 49.330 53.562 1.00 147.75 O Atom 1014 OE2 GLU A 397 81.872 50.445 51.883 1.00 144.18 O Atom 1015 C GLU A 397 78.067 46.469 50.759 1.00 129.90 C Atom 1016 O GLU A 397 77.600 47.601 50.895 1.00 123.43 O Atom 1017 N PRO A 398 77.337 45.426 50.330 1.00 127.48 N Atom 1018 CA PRO A 398 75.887 45.458 50.145 1.00 113.62 C Atom 1019 CB PRO A 398 75.712 44.623 48.886 1.00 103.52 C Atom 1020 CG PRO A 398 76.732 43.526 49.073 1.00 115.07 C Atom 1021 CD PRO A 398 77.889 44.135 49.878 1.00 119.12 C Atom 1022 C PRO A 398 75.190 44.775 51.314 1.00 103.10 C Atom 1023 O PRO A 398 74.106 44.220 51.140 1.00 106.49 O Atom 1024 N LYS A 399 75.827 44.817 52.482 1.00 105.66 N Atom 1025 CA LYS A 399 75.306 44.235 53.724 1.00 96.49 C Atom 1026 CB LYS A 399 74.203 45.108 54.343 1.00 94.11 C Atom 1027 CG LYS A 399 72.955 45.276 53.493 1.00 106.89 C Atom 1028 CD LYS A 399 71.866 46.031 54.236 1.00 114.53 C Atom 1029 CE LYS A 399 70.551 45.967 53.479 1.00 116.89 C Atom 1030 NZ LYS A 399 70.198 44.560 53.126 1.00 97.55 N Atom 1031 C LYS A 399 74.866 42.771 53.624 1.00 92.60 C Atom 1032 O LYS A 399 73.925 42.437 52.906 1.00 93.10 O Atom 1033 N PRO A 400 75.553 41.894 54.369 1.00 87.25 N Atom 1034 CA PRO A 400 75.313 40.449 54.349 1.00 83.83 C Atom 1035 CB PRO A 400 76.628 39.876 54.875 1.00 78.85 C Atom 1036 CG PRO A 400 77.176 40.945 55.764 1.00 81.58 C Atom 1037 CD PRO A 400 76.638 42.268 55.293 1.00 79.87 C Atom 1038 C PRO A 400 74.167 40.027 55.263 1.00 81.54 C Atom 1039 O PRO A 400 73.942 40.642 56.307 1.00 81.24 O Atom 1040 N ARG A 401 73.456 38.979 54.861 1.00 79.78 N Atom 1041 CA ARG A 401 72.385 38.405 55.666 1.00 72.29 C Atom 1042 CB ARG A 401 71.024 38.751 55.065 1.00 70.66 C Atom 1043 CG ARG A 401 70.678 40.228 55.128 1.00 72.33 C Atom 1044 CD ARG A 401 70.423 40.672 56.558 1.00 69.81 C Atom 1045 NE ARG A 401 70.140 42.101 56.629 1.00 81.24 N Atom 1046 CZ ARG A 401 68.954 42.642 56.370 1.00 92.20 C Atom 1047 NH1 ARG A 401 67.933 41.870 56.018 1.00 74.99 N Atom 1048 NH2 ARG A 401 68.790 43.955 56.461 1.00 93.37 N Atom 1049 C ARG A 401 72.548 36.892 55.740 1.00 72.21 C Atom 1050 O ARG A 401 73.023 36.265 54.794 1.00 76.72 O Atom 1051 N SER A 402 72.155 36.303 56.863 1.00 68.12 N Atom 1052 CA SER A 402 72.271 34.859 57.033 1.00 70.31 C Atom 1053 CB SER A 402 72.651 34.520 58.473 1.00 71.40 C Atom 1054 OG SER A 402 71.736 35.107 59.380 1.00 79.39 O Atom 1055 C SER A 402 70.981 34.139 56.645 1.00 69.11 C Atom 1056 O SER A 402 69.905 34.736 56.632 1.00 73.27 O Atom 1057 N LEU A 403 71.100 32.856 56.318 1.00 70.48 N Atom 1058 CA LEU A 403 69.946 32.056 55.922 1.00 67.84 C Atom 1059 CB LEU A 403 70.384 30.660 55.474 1.00 65.53 C Atom 1060 CG LEU A 403 69.258 29.708 55.064 1.00 62.36 C Atom 1061 CD1 LEU A 403 68.499 30.265 53.867 1.00 62.62 C Atom 1062 CD2 LEU A 403 69.799 28.321 54.762 1.00 56.24 C Atom 1063 C LEU A 403 68.968 31.932 57.080 1.00 66.40 C Atom 1064 O LEU A 403 69.378 31.808 58.235 1.00 70.82 O Atom 1065 N ALA A 404 67.678 31.976 56.766 1.00 69.28 N Atom 1066 CA ALA A 404 66.632 31.776 57.760 1.00 65.28 C Atom 1067 CB ALA A 404 65.833 33.050 57.954 1.00 63.64 C Atom 1068 C ALA A 404 65.725 30.638 57.312 1.00 66.90 C Atom 1069 O ALA A 404 65.592 30.371 56.117 1.00 70.46 O Atom 1070 N SER A 405 65.090 29.978 58.274 1.00 65.64 N Atom 1071 CA SER A 405 64.262 28.813 57.983 1.00 61.41 C Atom 1072 CB SER A 405 63.838 28.125 59.284 1.00 61.33 C Atom 1073 OG SER A 405 63.409 29.071 60.248 1.00 61.56 O Atom 1074 C SER A 405 63.034 29.139 57.132 1.00 60.17 C Atom 1075 O SER A 405 62.480 28.259 56.471 1.00 57.99 O Atom 1076 N TRP A 406 62.615 30.400 57.136 1.00 60.23 N Atom 1077 CA TRP A 406 61.376 30.767 56.457 1.00 60.39 C Atom 1078 CB TRP A 406 60.965 32.221 56.750 1.00 60.11 C Atom 1079 CG TRP A 406 61.788 33.280 56.074 1.00 60.50 C Atom 1080 CD1 TRP A 406 62.778 34.034 56.638 1.00 62.85 C Atom 1081 NE1 TRP A 406 63.293 34.907 55.713 1.00 59.69 N Atom 1082 CE2 TRP A 406 62.635 34.737 54.527 1.00 59.85 C Atom 1083 CD2 TRP A 406 61.674 33.722 54.713 1.00 59.79 C Atom 1084 CE3 TRP A 406 60.861 33.353 53.638 1.00 58.10 C Atom 1085 CZ3 TRP A 406 61.030 34.001 52.426 1.00 59.83 C Atom 1086 CH2 TRP A 406 61.994 35.005 52.268 1.00 61.83 C Atom 1087 CZ2 TRP A 406 62.805 35.385 53.302 1.00 58.84 C Atom 1088 C TRP A 406 61.384 30.474 54.955 1.00 58.72 C Atom 1089 O TRP A 406 60.367 30.062 54.399 1.00 62.12 O Atom 1090 N ILE A 407 62.526 30.668 54.303 1.00 59.80 N Atom 1091 CA ILE A 407 62.614 30.443 52.861 1.00 57.57 C Atom 1092 CB ILE A 407 63.940 30.976 52.270 1.00 58.50 C Atom 1093 CG1 ILE A 407 63.959 30.786 50.752 1.00 54.84 C Atom 1094 CD1 ILE A 407 62.814 31.464 50.041 1.00 53.56 C Atom 1095 CG2 ILE A 407 65.137 30.298 52.916 1.00 62.99 C Atom 1096 C ILE A 407 62.417 28.971 52.481 1.00 55.86 C Atom 1097 O ILE A 407 61.844 28.664 51.434 1.00 55.21 O Atom 1098 N GLN A 408 62.887 28.062 53.332 1.00 56.99 N Atom 1099 CA GLN A 408 62.680 26.634 53.094 1.00 59.81 C Atom 1100 CB GLN A 408 63.556 25.779 54.014 1.00 54.96 C Atom 1101 CG GLN A 408 63.236 24.282 53.971 1.00 57.53 C Atom 1102 CD GLN A 408 63.763 23.589 52.722 1.00 64.31 C Atom 1103 OE1 GLN A 408 64.968 23.574 52.467 1.00 63.01 O Atom 1104 NE2 GLN A 408 62.860 22.998 51.944 1.00 58.84 N Atom 1105 C GLN A 408 61.208 26.258 53.266 1.00 59.50 C Atom 1106 O GLN A 408 60.668 25.463 52.495 1.00 56.46 O Atom 1107 N SER A 409 60.568 26.831 54.282 1.00 59.11 N Atom 1108 CA SER A 409 59.135 26.657 54.474 1.00 60.23 C Atom 1109 CB SER A 409 58.657 27.441 55.693 1.00 59.96 C Atom 1110 OG SER A 409 59.283 26.973 56.869 1.00 73.64 O Atom 1111 C SER A 409 58.391 27.129 53.235 1.00 60.83 C Atom 1112 O SER A 409 57.507 26.437 52.725 1.00 56.40 O Atom 1113 N GLU A 410 58.757 28.316 52.762 1.00 55.80 N Atom 1114 CA GLU A 410 58.173 28.868 51.550 1.00 60.04 C Atom 1115 CB GLU A 410 58.916 30.136 51.128 1.00 56.93 C Atom 1116 CG GLU A 410 58.578 31.360 51.958 1.00 54.07 C Atom 1117 CD GLU A 410 57.204 31.923 51.648 1.00 57.31 C Atom 1118 OE1 GLU A 410 56.386 31.219 51.017 1.00 62.02 O Atom 1119 OE2 GLU A 410 56.939 33.079 52.038 1.00 63.53 O Atom 1120 C GLU A 410 58.194 27.851 50.419 1.00 62.55 C Atom 1121 O GLU A 410 57.175 27.610 49.776 1.00 67.91 O Atom 1122 N PHE A 411 59.358 27.255 50.184 1.00 57.41 N Atom 1123 CA PHE A 411 59.514 26.297 49.096 1.00 58.35 C Atom 1124 CB PHE A 411 60.990 25.979 48.850 1.00 60.55 C Atom 1125 CG PHE A 411 61.237 25.215 47.580 1.00 60.15 C Atom 1126 CD1 PHE A 411 61.109 25.838 46.349 1.00 58.70 C Atom 1127 CE1 PHE A 411 61.333 25.143 45.181 1.00 58.31 C Atom 1128 CZ PHE A 411 61.689 23.811 45.229 1.00 59.78 C Atom 1129 CE2 PHE A 411 61.821 23.178 46.448 1.00 58.74 C Atom 1130 CD2 PHE A 411 61.596 23.879 47.615 1.00 57.79 C Atom 1131 C PHE A 411 58.729 25.011 49.345 1.00 60.33 C Atom 1132 O PHE A 411 58.133 24.450 48.425 1.00 58.90 O Atom 1133 N ASN A 412 58.741 24.544 50.589 1.00 61.13 N Atom 1134 CA ASN A 412 57.949 23.382 50.975 1.00 56.59 C Atom 1135 CB ASN A 412 58.046 23.139 52.481 1.00 52.28 C Atom 1136 CG ASN A 412 59.403 22.615 52.899 1.00 59.84 C Atom 1137 OD1 ASN A 412 60.112 21.995 52.107 1.00 64.47 O Atom 1138 ND2 ASN A 412 59.770 22.856 54.152 1.00 59.12 N Atom 1139 C ASN A 412 56.490 23.559 50.574 1.00 61.50 C Atom 1140 O ASN A 412 55.913 22.708 49.894 1.00 58.46 O Atom 1141 N LYS A 413 55.901 24.672 50.999 1.00 62.06 N Atom 1142 CA LYS A 413 54.509 24.971 50.693 1.00 63.34 C Atom 1143 CB LYS A 413 54.086 26.274 51.371 1.00 66.11 C Atom 1144 CG LYS A 413 54.419 26.355 52.853 1.00 66.44 C Atom 1145 CD LYS A 413 53.215 26.072 53.735 1.00 75.20 C Atom 1146 CE LYS A 413 52.851 24.602 53.760 1.00 78.20 C Atom 1147 NZ LYS A 413 51.618 24.370 54.572 1.00 87.98 N Atom 1148 C LYS A 413 54.300 25.096 49.190 1.00 66.20 C Atom 1149 O LYS A 413 53.209 24.835 48.683 1.00 68.19 O Atom 1150 N ALA A 414 55.348 25.506 48.482 1.00 63.27 N Atom 1151 CA ALA A 414 55.272 25.699 47.037 1.00 62.45 C Atom 1152 CB ALA A 414 56.492 26.452 46.538 1.00 57.36 C Atom 1153 C ALA A 414 55.126 24.372 46.295 1.00 61.74 C Atom 1154 O ALA A 414 54.575 24.325 45.195 1.00 58.30 O Atom 1155 N CYS A 415 55.623 23.298 46.901 1.00 62.99 N Atom 1156 CA CYS A 415 55.564 21.973 46.293 1.00 66.59 C Atom 1157 CB CYS A 415 56.748 21.124 46.754 1.00 61.51 C Atom 1158 SG CYS A 415 58.358 21.758 46.264 1.00 67.86 S Atom 1159 C CYS A 415 54.267 21.255 46.636 1.00 69.78 C Atom 1160 O CYS A 415 54.000 20.167 46.129 1.00 69.29 O Atom 1161 N GLU A 416 53.466 21.869 47.500 1.00 70.43 N Atom 1162 CA GLU A 416 52.236 21.251 47.981 1.00 62.53 C Atom 1163 CB GLU A 416 51.761 21.935 49.262 1.00 64.49 C Atom 1164 CG GLU A 416 52.572 21.587 50.493 1.00 69.11 C Atom 1165 CD GLU A 416 51.945 22.117 51.771 1.00 82.89 C Atom 1166 OE1 GLU A 416 50.984 22.915 51.679 1.00 78.69 O Atom 1167 OE2 GLU A 416 52.411 21.732 52.867 1.00 85.51 O Atom 1168 C GLU A 416 51.115 21.274 46.952 1.00 68.50 C Atom 1169 O GLU A 416 51.096 22.110 46.049 1.00 67.59 O Atom 1170 N LEU A 417 50.181 20.339 47.100 1.00 74.95 N Atom 1171 CA LEU A 417 48.982 20.305 46.276 1.00 71.69 C Atom 1172 CB LEU A 417 48.482 18.869 46.107 1.00 72.24 C Atom 1173 CG LEU A 417 49.194 18.039 45.038 1.00 78.14 C Atom 1174 CD1 LEU A 417 48.882 16.555 45.185 1.00 69.20 C Atom 1175 CD2 LEU A 417 48.829 18.540 43.646 1.00 75.78 C Atom 1176 C LEU A 417 47.900 21.168 46.906 1.00 74.07 C Atom 1177 O LEU A 417 47.807 21.269 48.129 1.00 73.16 O Atom 1178 N THR A 418 47.086 21.788 46.060 1.00 74.30 N Atom 1179 CA THR A 418 46.013 22.665 46.508 1.00 73.87 C Atom 1180 CB THR A 418 46.109 24.049 45.818 1.00 72.38 C Atom 1181 OG1 THR A 418 47.171 24.804 46.413 1.00 74.49 O Atom 1182 CG2 THR A 418 44.810 24.833 45.955 1.00 81.97 C Atom 1183 C THR A 418 44.656 22.025 46.228 1.00 80.68 C Atom 1184 O THR A 418 44.544 21.136 45.386 1.00 82.74 O Atom 1185 N ASP A 419 43.632 22.462 46.953 1.00 81.64 N Atom 1186 CA ASP A 419 42.274 22.005 46.700 1.00 84.73 C Atom 1187 CB ASP A 419 41.427 22.121 47.970 1.00 91.30 C Atom 1188 CG ASP A 419 41.759 21.049 48.995 1.00 99.95 C Atom 1189 OD1 ASP A 419 42.252 19.972 48.592 1.00 94.63 O Atom 1190 OD2 ASP A 419 41.521 21.281 50.200 1.00 99.60 O Atom 1191 C ASP A 419 41.635 22.797 45.563 1.00 83.71 C Atom 1192 O ASP A 419 40.425 23.023 45.561 1.00 92.50 O Atom 1193 N SER A 420 42.452 23.219 44.601 1.00 80.83 N Atom 1194 CA SER A 420 41.963 23.990 43.460 1.00 83.70 C Atom 1195 CB SER A 420 41.838 25.474 43.815 1.00 77.99 C Atom 1196 OG SER A 420 40.682 25.724 44.595 1.00 79.92 O Atom 1197 C SER A 420 42.855 23.832 42.235 1.00 79.20 C Atom 1198 O SER A 420 44.061 23.633 42.355 1.00 83.32 O Atom 1199 N SER A 421 42.245 23.922 41.059 1.00 82.45 N Atom 1200 CA SER A 421 42.973 23.869 39.799 1.00 83.16 C Atom 1201 CB SER A 421 42.170 23.105 38.745 1.00 87.39 C Atom 1202 OG SER A 421 42.775 23.201 37.467 1.00 92.51 O Atom 1203 C SER A 421 43.251 25.286 39.320 1.00 79.62 C Atom 1204 O SER A 421 42.390 26.162 39.416 1.00 75.20 O Atom 1205 N TRP A 422 44.454 25.507 38.802 1.00 81.97 N Atom 1206 CA TRP A 422 44.883 26.853 38.439 1.00 77.24 C Atom 1207 CB TRP A 422 46.131 27.247 39.233 1.00 70.52 C Atom 1208 CG TRP A 422 45.873 27.276 40.705 1.00 65.86 C Atom 1209 CD1 TRP A 422 46.088 26.264 41.593 1.00 64.70 C Atom 1210 NE1 TRP A 422 45.718 26.659 42.855 1.00 65.01 N Atom 1211 CE2 TRP A 422 45.245 27.944 42.800 1.00 60.70 C Atom 1212 CD2 TRP A 422 45.325 28.364 41.459 1.00 62.81 C Atom 1213 CE3 TRP A 422 44.900 29.657 41.132 1.00 63.01 C Atom 1214 CZ3 TRP A 422 44.418 30.474 42.142 1.00 63.07 C Atom 1215 CH2 TRP A 422 44.349 30.023 43.466 1.00 61.23 C Atom 1216 CZ2 TRP A 422 44.758 28.765 43.814 1.00 61.38 C Atom 1217 C TRP A 422 45.119 27.014 36.943 1.00 80.71 C Atom 1218 O TRP A 422 45.360 28.122 36.464 1.00 81.01 O Atom 1219 N ILE A 423 45.032 25.911 36.207 1.00 89.85 N Atom 1220 CA ILE A 423 45.250 25.937 34.765 1.00 95.06 C Atom 1221 CB ILE A 423 46.722 25.638 34.421 1.00 91.38 C Atom 1222 CG1 ILE A 423 47.183 24.364 35.135 1.00 84.51 C Atom 1223 CD1 ILE A 423 48.600 23.951 34.794 1.00 84.35 C Atom 1224 CG2 ILE A 423 47.611 26.812 34.800 1.00 84.21 C Atom 1225 C ILE A 423 44.378 24.921 34.036 1.00 106.56 C Atom 1226 O ILE A 423 44.100 23.842 34.558 1.00 105.08 O Atom 1227 N GLU A 424 43.949 25.273 32.827 1.00 118.30 N Atom 1228 CA GLU A 424 43.246 24.336 31.959 1.00 126.00 C Atom 1229 CB GLU A 424 42.750 25.047 30.698 1.00 133.89 C Atom 1230 CG GLU A 424 41.639 24.321 29.951 1.00 147.95 C Atom 1231 CD GLU A 424 40.256 24.677 30.468 1.00 159.12 C Atom 1232 OE1 GLU A 424 39.274 24.029 30.043 1.00 156.29 O Atom 1233 OE2 GLU A 424 40.151 25.607 31.296 1.00 154.83 O Atom 1234 C GLU A 424 44.224 23.225 31.587 1.00 128.54 C Atom 1235 O GLU A 424 45.435 23.393 31.735 1.00 121.99 O Atom 1236 N LEU A 425 43.712 22.096 31.105 1.00 132.83 N Atom 1237 CA LEU A 425 44.570 20.949 30.797 1.00 133.23 C Atom 1238 CB LEU A 425 43.744 19.708 30.454 1.00 137.36 C Atom 1239 CG LEU A 425 43.198 18.939 31.657 1.00 146.11 C Atom 1240 CD1 LEU A 425 41.792 19.410 32.006 1.00 142.64 C Atom 1241 CD2 LEU A 425 43.214 17.443 31.384 1.00 132.46 C Atom 1242 C LEU A 425 45.598 21.223 29.700 1.00 134.04 C Atom 1243 O LEU A 425 46.577 20.487 29.559 1.00 123.82 O Atom 1244 N ASP A 426 45.370 22.274 28.920 1.00 144.28 N Atom 1245 CA ASP A 426 46.356 22.721 27.941 1.00 146.33 C Atom 1246 CB ASP A 426 45.783 22.680 26.521 1.00 149.70 C Atom 1247 CG ASP A 426 44.292 22.953 26.486 1.00 153.00 C Atom 1248 OD1 ASP A 426 43.868 24.020 26.979 1.00 154.59 O Atom 1249 OD2 ASP A 426 43.546 22.098 25.960 1.00 154.15 O Atom 1250 C ASP A 426 46.871 24.116 28.296 1.00 148.80 C Atom 1251 O ASP A 426 46.996 24.450 29.474 1.00 147.26 O Atom 1252 N GLU A 427 47.175 24.927 27.288 1.00 152.67 N Atom 1253 CA GLU A 427 47.669 26.279 27.543 1.00 157.07 C Atom 1254 CB GLU A 427 49.007 26.528 26.838 1.00 155.31 C Atom 1255 CG GLU A 427 50.177 25.757 27.431 1.00 154.80 C Atom 1256 CD GLU A 427 50.582 24.564 26.588 1.00 153.62 C Atom 1257 OE1 GLU A 427 51.164 24.776 25.502 1.00 146.73 O Atom 1258 OE2 GLU A 427 50.328 23.418 27.015 1.00 147.06 O Atom 1259 C GLU A 427 46.659 27.361 27.168 1.00 159.19 C Atom 1260 O GLU A 427 47.002 28.339 26.504 1.00 156.38 O Atom 1261 N ILE A 428 45.414 27.178 27.598 1.00 156.03 N Atom 1262 CA ILE A 428 44.377 28.185 27.397 1.00 158.60 C Atom 1263 CB ILE A 428 42.970 27.558 27.343 1.00 158.12 C Atom 1264 CG1 ILE A 428 42.544 27.332 25.890 1.00 157.10 C Atom 1265 CD1 ILE A 428 41.089 26.938 25.729 1.00 153.34 C Atom 1266 CG2 ILE A 428 41.960 28.453 28.042 1.00 155.63 C Atom 1267 C ILE A 428 44.417 29.240 28.499 1.00 159.79 C Atom 1268 O ILE A 428 45.462 29.835 28.765 1.00 153.55 O Atom 1269 N ILE A 438 51.730 12.107 20.694 1.00 134.66 N Atom 1270 CA ILE A 438 52.908 11.268 20.887 1.00 144.95 C Atom 1271 CB ILE A 438 53.976 11.533 19.804 1.00 146.99 C Atom 1272 CG1 ILE A 438 54.136 13.037 19.566 1.00 138.72 C Atom 1273 CD1 ILE A 438 55.315 13.397 18.688 1.00 133.80 C Atom 1274 CG2 ILE A 438 53.602 10.832 18.504 1.00 136.55 C Atom 1275 C ILE A 438 53.505 11.477 22.277 1.00 143.35 C Atom 1276 O ILE A 438 53.114 10.809 23.237 1.00 138.80 O Atom 1277 N ALA A 439 54.459 12.398 22.377 1.00 145.09 N Atom 1278 CA ALA A 439 54.986 12.822 23.666 1.00 138.34 C Atom 1279 CB ALA A 439 56.380 13.412 23.509 1.00 138.91 C Atom 1280 C ALA A 439 54.031 13.845 24.265 1.00 131.03 C Atom 1281 O ALA A 439 54.184 14.264 25.413 1.00 129.61 O Atom 1282 N SER A 440 53.044 14.245 23.467 1.00 131.32 N Atom 1283 CA SER A 440 51.957 15.097 23.934 1.00 130.85 C Atom 1284 CB SER A 440 50.929 15.302 22.821 1.00 136.55 C Atom 1285 OG SER A 440 49.646 15.578 23.356 1.00 136.71 O Atom 1286 C SER A 440 51.290 14.451 25.138 1.00 123.39 C Atom 1287 O SER A 440 50.687 15.124 25.973 1.00 124.44 O Atom 1288 N MET A 441 51.404 13.131 25.212 1.00 119.60 N Atom 1289 CA MET A 441 50.879 12.365 26.332 1.00 123.66 C Atom 1290 CB MET A 441 50.997 10.869 26.037 1.00 125.49 C Atom 1291 CG MET A 441 51.494 10.016 27.187 1.00 121.45 C Atom 1292 SD MET A 441 51.048 8.289 26.929 1.00 146.20 S Atom 1293 CE MET A 441 52.565 7.458 27.393 1.00 136.66 C Atom 1294 C MET A 441 51.583 12.726 27.638 1.00 121.69 C Atom 1295 O MET A 441 50.960 12.752 28.700 1.00 120.56 O Atom 1296 N ARG A 442 52.879 13.012 27.551 1.00 123.33 N Atom 1297 CA ARG A 442 53.656 13.433 28.713 1.00 120.11 C Atom 1298 CB ARG A 442 55.136 13.543 28.350 1.00 120.64 C Atom 1299 CG ARG A 442 55.803 12.212 28.065 1.00 120.48 C Atom 1300 CD ARG A 442 56.829 12.346 26.955 1.00 127.60 C Atom 1301 NE ARG A 442 57.584 11.113 26.761 1.00 132.60 N Atom 1302 CZ ARG A 442 58.887 10.995 26.984 1.00 126.21 C Atom 1303 NH1 ARG A 442 59.587 12.043 27.396 1.00 123.25 N Atom 1304 NH2 ARG A 442 59.493 9.832 26.784 1.00 129.47 N Atom 1305 C ARG A 442 53.148 14.767 29.246 1.00 114.23 C Atom 1306 O ARG A 442 52.962 14.934 30.451 1.00 111.51 O Atom 1307 N ARG A 443 52.933 15.715 28.339 1.00 111.92 N Atom 1308 CA ARG A 443 52.349 16.999 28.697 1.00 107.28 C Atom 1309 CB ARG A 443 51.928 17.759 27.440 1.00 115.03 C Atom 1310 CG ARG A 443 51.155 19.037 27.721 1.00 123.70 C Atom 1311 CD ARG A 443 50.074 19.266 26.675 1.00 134.81 C Atom 1312 NE ARG A 443 50.623 19.428 25.332 1.00 146.53 N Atom 1313 CZ ARG A 443 49.917 19.273 24.216 1.00 142.46 C Atom 1314 NH1 ARG A 443 48.634 18.939 24.281 1.00 138.28 N Atom 1315 NH2 ARG A 443 50.494 19.442 23.034 1.00 137.12 N Atom 1316 C ARG A 443 51.133 16.783 29.590 1.00 106.19 C Atom 1317 O ARG A 443 50.989 17.423 30.631 1.00 104.04 O Atom 1318 N ASN A 444 50.263 15.869 29.171 1.00 108.06 N Atom 1319 CA ASN A 444 49.052 15.555 29.918 1.00 110.85 C Atom 1320 CB ASN A 444 48.209 14.524 29.163 1.00 118.29 C Atom 1321 CG ASN A 444 47.572 15.097 27.912 1.00 122.57 C Atom 1322 OD1 ASN A 444 47.527 16.313 27.726 1.00 122.36 O Atom 1323 ND2 ASN A 444 47.072 14.221 27.047 1.00 126.42 N Atom 1324 C ASN A 444 49.338 15.070 31.336 1.00 105.36 C Atom 1325 O ASN A 444 48.826 15.631 32.304 1.00 101.91 O Atom 1326 N TYR A 445 50.153 14.025 31.454 1.00 105.18 N Atom 1327 CA TYR A 445 50.521 13.488 32.762 1.00 105.34 C Atom 1328 CB TYR A 445 51.570 12.381 32.624 1.00 110.91 C Atom 1329 CG TYR A 445 50.995 11.004 32.390 1.00 116.63 C Atom 1330 CD1 TYR A 445 51.288 10.293 31.232 1.00 124.04 C Atom 1331 CE1 TYR A 445 50.764 9.031 31.017 1.00 129.17 C Atom 1332 CZ TYR A 445 49.935 8.467 31.965 1.00 131.25 C Atom 1333 OH TYR A 445 49.409 7.212 31.756 1.00 134.17 O Atom 1334 CE2 TYR A 445 49.631 9.155 33.123 1.00 124.23 C Atom 1335 CD2 TYR A 445 50.160 10.414 33.328 1.00 115.10 C Atom 1336 C TYR A 445 51.056 14.586 33.674 1.00 103.86 C Atom 1337 O TYR A 445 50.580 14.767 34.797 1.00 101.42 O Atom 1338 N PHE A 446 52.055 15.309 33.179 1.00 101.45 N Atom 1339 CA PHE A 446 52.673 16.401 33.920 1.00 94.81 C Atom 1340 CB PHE A 446 53.722 17.096 33.045 1.00 95.04 C Atom 1341 CG PHE A 446 54.341 18.310 33.678 1.00 91.77 C Atom 1342 CD1 PHE A 446 55.384 18.183 34.579 1.00 88.17 C Atom 1343 CE1 PHE A 446 55.958 19.298 35.156 1.00 88.62 C Atom 1344 CZ PHE A 446 55.494 20.556 34.834 1.00 84.70 C Atom 1345 CE2 PHE A 446 54.458 20.697 33.935 1.00 80.69 C Atom 1346 CD2 PHE A 446 53.888 19.580 33.360 1.00 86.09 C Atom 1347 C PHE A 446 51.630 17.404 34.411 1.00 94.62 C Atom 1348 O PHE A 446 51.603 17.759 35.589 1.00 90.04 O Atom 1349 N THR A 447 50.766 17.848 33.504 1.00 91.21 N Atom 1350 CA THR A 447 49.738 18.829 33.834 1.00 87.48 C Atom 1351 CB THR A 447 48.925 19.233 32.594 1.00 88.79 C Atom 1352 OG1 THR A 447 49.811 19.701 31.571 1.00 92.55 O Atom 1353 CG2 THR A 447 47.937 20.334 32.945 1.00 91.21 C Atom 1354 C THR A 447 48.780 18.311 34.903 1.00 85.00 C Atom 1355 O THR A 447 48.367 19.053 35.792 1.00 86.50 O Atom 1356 N ALA A 448 48.425 17.035 34.811 1.00 90.88 N Atom 1357 CA ALA A 448 47.529 16.427 35.785 1.00 95.60 C Atom 1358 CB ALA A 448 47.139 15.025 35.339 1.00 95.49 C Atom 1359 C ALA A 448 48.185 16.387 37.158 1.00 91.24 C Atom 1360 O ALA A 448 47.514 16.242 38.179 1.00 89.22 O Atom 1361 N GLU A 449 49.506 16.527 37.171 1.00 87.90 N Atom 1362 CA GLU A 449 50.283 16.369 38.390 1.00 83.30 C Atom 1363 CB GLU A 449 51.523 15.528 38.098 1.00 84.15 C Atom 1364 CG GLU A 449 52.092 14.833 39.308 1.00 89.88 C Atom 1365 CD GLU A 449 51.353 13.555 39.639 1.00 88.78 C Atom 1366 OE1 GLU A 449 50.898 12.870 38.698 1.00 95.32 O Atom 1367 OE2 GLU A 449 51.232 13.233 40.839 1.00 86.76 O Atom 1368 C GLU A 449 50.702 17.713 38.981 1.00 80.75 C Atom 1369 O GLU A 449 51.264 17.772 40.076 1.00 76.83 O Atom 1370 N VAL A 450 50.415 18.790 38.258 1.00 83.63 N Atom 1371 CA VAL A 450 50.924 20.111 38.618 1.00 79.89 C Atom 1372 CB VAL A 450 52.087 20.513 37.678 1.00 73.63 C Atom 1373 CG1 VAL A 450 51.984 21.970 37.258 1.00 73.96 C Atom 1374 CG2 VAL A 450 53.430 20.208 38.333 1.00 70.48 C Atom 1375 C VAL A 450 49.854 21.210 38.646 1.00 80.79 C Atom 1376 O VAL A 450 50.043 22.258 39.267 1.00 73.34 O Atom 1377 N SER A 451 48.726 20.958 37.989 1.00 81.01 N Atom 1378 CA SER A 451 47.672 21.962 37.858 1.00 81.98 C Atom 1379 CB SER A 451 46.523 21.420 37.005 1.00 85.16 C Atom 1380 OG SER A 451 45.904 20.310 37.628 1.00 86.17 O Atom 1381 C SER A 451 47.139 22.448 39.207 1.00 81.74 C Atom 1382 O SER A 451 46.638 23.568 39.320 1.00 77.15 O Atom 1383 N HIS A 452 47.248 21.603 40.228 1.00 78.81 N Atom 1384 CA HIS A 452 46.751 21.942 41.558 1.00 76.60 C Atom 1385 CB HIS A 452 46.003 20.752 42.168 1.00 80.91 C Atom 1386 CG HIS A 452 44.657 20.499 41.552 1.00 89.72 C Atom 1387 ND1 HIS A 452 44.503 20.059 40.261 1.00 92.47 N Atom 1388 CE1 HIS A 452 43.210 19.922 39.997 1.00 86.51 C Atom 1389 NE2 HIS A 452 42.532 20.252 41.075 1.00 85.36 N Atom 1390 CD2 HIS A 452 43.411 20.617 42.070 1.00 85.53 C Atom 1391 C HIS A 452 47.885 22.369 42.486 1.00 78.41 C Atom 1392 O HIS A 452 47.675 22.586 43.675 1.00 78.50 O Atom 1393 N CYS A 453 49.088 22.488 41.936 1.00 71.44 N Atom 1394 CA CYS A 453 50.255 22.839 42.732 1.00 68.19 C Atom 1395 CB CYS A 453 51.533 22.510 41.959 1.00 70.20 C Atom 1396 SG CYS A 453 53.026 22.501 42.964 1.00 68.87 S Atom 1397 C CYS A 453 50.236 24.314 43.127 1.00 67.29 C Atom 1398 O CYS A 453 49.845 25.170 42.335 1.00 66.59 O Atom 1399 N ARG A 454 50.660 24.606 44.353 1.00 65.22 N Atom 1400 CA ARG A 454 50.696 25.984 44.836 1.00 64.95 C Atom 1401 CB ARG A 454 51.082 26.030 46.315 1.00 64.60 C Atom 1402 CG ARG A 454 51.242 27.432 46.869 1.00 60.61 C Atom 1403 CD ARG A 454 51.122 27.450 48.380 1.00 67.79 C Atom 1404 NE ARG A 454 49.793 27.043 48.831 1.00 75.17 N Atom 1405 CZ ARG A 454 49.529 25.889 49.438 1.00 73.62 C Atom 1406 NH1 ARG A 454 50.505 25.025 49.677 1.00 65.29 N Atom 1407 NH2 ARG A 454 48.289 25.604 49.812 1.00 75.83 N Atom 1408 C ARG A 454 51.657 26.830 44.005 1.00 63.07 C Atom 1409 O ARG A 454 51.458 28.034 43.838 1.00 60.75 O Atom 1410 N ALA A 455 52.700 26.193 43.483 1.00 61.62 N Atom 1411 CA ALA A 455 53.624 26.871 42.586 1.00 58.00 C Atom 1412 CB ALA A 455 54.724 25.927 42.141 1.00 58.04 C Atom 1413 C ALA A 455 52.863 27.417 41.383 1.00 62.13 C Atom 1414 O ALA A 455 53.118 28.526 40.919 1.00 61.14 O Atom 1415 N THR A 456 51.913 26.629 40.890 1.00 67.41 N Atom 1416 CA THR A 456 51.112 27.027 39.739 1.00 64.51 C Atom 1417 CB THR A 456 50.230 25.877 39.230 1.00 65.80 C Atom 1418 OG1 THR A 456 51.045 24.723 38.996 1.00 72.08 O Atom 1419 CG2 THR A 456 49.538 26.273 37.935 1.00 64.08 C Atom 1420 C THR A 456 50.235 28.232 40.061 1.00 63.57 C Atom 1421 O THR A 456 50.042 29.107 39.214 1.00 68.58 O Atom 1422 N GLU A 457 49.702 28.278 41.279 1.00 60.16 N Atom 1423 CA GLU A 457 48.950 29.451 41.713 1.00 60.54 C Atom 1424 CB GLU A 457 48.420 29.284 43.136 1.00 56.14 C Atom 1425 CG GLU A 457 47.762 30.550 43.667 1.00 54.33 C Atom 1426 CD GLU A 457 47.362 30.445 45.121 1.00 57.35 C Atom 1427 OE1 GLU A 457 47.634 29.395 45.743 1.00 59.90 O Atom 1428 OE2 GLU A 457 46.773 31.416 45.644 1.00 54.85 O Atom 1429 C GLU A 457 49.833 30.688 41.639 1.00 62.33 C Atom 1430 O GLU A 457 49.414 31.732 41.145 1.00 59.18 O Atom 1431 N TYR A 458 51.059 30.559 42.141 1.00 60.76 N Atom 1432 CA TYR A 458 52.015 31.660 42.114 1.00 63.39 C Atom 1433 CB TYR A 458 53.349 31.258 42.756 1.00 59.65 C Atom 1434 CG TYR A 458 53.245 30.950 44.233 1.00 58.63 C Atom 1435 CD1 TYR A 458 52.232 31.506 45.003 1.00 55.98 C Atom 1436 CE1 TYR A 458 52.129 31.234 46.353 1.00 52.56 C Atom 1437 CZ TYR A 458 53.053 30.407 46.956 1.00 56.38 C Atom 1438 OH TYR A 458 52.948 30.137 48.302 1.00 53.19 O Atom 1439 CE2 TYR A 458 54.076 29.848 46.216 1.00 57.03 C Atom 1440 CD2 TYR A 458 54.170 30.123 44.863 1.00 54.96 C Atom 1441 C TYR A 458 52.239 32.157 40.690 1.00 65.69 C Atom 1442 O TYR A 458 52.317 33.363 40.451 1.00 62.51 O Atom 1443 N ILE A 459 52.337 31.222 39.747 1.00 64.41 N Atom 1444 CA ILE A 459 52.492 31.568 38.337 1.00 66.13 C Atom 1445 CB ILE A 459 52.569 30.315 37.447 1.00 65.62 C Atom 1446 CG1 ILE A 459 53.922 29.623 37.620 1.00 69.39 C Atom 1447 CD1 ILE A 459 54.067 28.350 36.813 1.00 65.19 C Atom 1448 CG2 ILE A 459 52.344 30.685 35.988 1.00 69.09 C Atom 1449 C ILE A 459 51.339 32.440 37.855 1.00 70.68 C Atom 1450 O ILE A 459 51.549 33.532 37.322 1.00 67.76 O Atom 1451 N MET A 460 50.119 31.952 38.051 1.00 68.68 N Atom 1452 CA MET A 460 48.927 32.660 37.597 1.00 69.35 C Atom 1453 CB MET A 460 47.695 31.770 37.738 1.00 71.59 C Atom 1454 CG MET A 460 47.772 30.492 36.914 1.00 74.07 C Atom 1455 SD MET A 460 48.214 30.800 35.193 1.00 76.73 S Atom 1456 CE MET A 460 46.958 31.987 34.717 1.00 78.74 C Atom 1457 C MET A 460 48.723 33.967 38.356 1.00 68.48 C Atom 1458 O MET A 460 48.324 34.978 37.774 1.00 69.99 O Atom 1459 N LYS A 461 48.990 33.939 39.657 1.00 68.31 N Atom 1460 CA LYS A 461 48.933 35.142 40.475 1.00 69.71 C Atom 1461 CB LYS A 461 49.337 34.816 41.913 1.00 68.71 C Atom 1462 CG LYS A 461 49.182 35.967 42.892 1.00 61.84 C Atom 1463 CD LYS A 461 49.494 35.513 44.309 1.00 58.11 C Atom 1464 CE LYS A 461 49.349 36.653 45.299 1.00 54.99 C Atom 1465 NZ LYS A 461 49.740 36.238 46.672 1.00 56.77 N Atom 1466 C LYS A 461 49.854 36.208 39.891 1.00 69.55 C Atom 1467 O LYS A 461 49.487 37.376 39.800 1.00 67.54 O Atom 1468 N GLY A 462 51.049 35.786 39.488 1.00 70.83 N Atom 1469 CA GLY A 462 52.027 36.681 38.898 1.00 67.24 C Atom 1470 C GLY A 462 51.630 37.190 37.525 1.00 71.56 C Atom 1471 O GLY A 462 51.877 38.348 37.190 1.00 75.96 O Atom 1472 N VAL A 463 51.017 36.323 36.726 1.00 72.44 N Atom 1473 CA VAL A 463 50.559 36.704 35.394 1.00 73.59 C Atom 1474 CB VAL A 463 50.015 35.493 34.615 1.00 68.22 C Atom 1475 CG1 VAL A 463 49.380 35.942 33.309 1.00 68.97 C Atom 1476 CG2 VAL A 463 51.124 34.494 34.354 1.00 71.53 C Atom 1477 C VAL A 463 49.482 37.785 35.467 1.00 75.68 C Atom 1478 O VAL A 463 49.570 38.813 34.796 1.00 73.47 O Atom 1479 N TYR A 464 48.471 37.546 36.296 1.00 74.32 N Atom 1480 CA TYR A 464 47.349 38.469 36.436 1.00 76.03 C Atom 1481 CB TYR A 464 46.319 37.911 37.420 1.00 74.37 C Atom 1482 CG TYR A 464 45.254 37.049 36.781 1.00 85.48 C Atom 1483 CD1 TYR A 464 45.581 35.843 36.169 1.00 86.40 C Atom 1484 CE1 TYR A 464 44.607 35.050 35.584 1.00 87.20 C Atom 1485 CZ TYR A 464 43.288 35.458 35.612 1.00 95.56 C Atom 1486 OH TYR A 464 42.312 34.676 35.035 1.00 97.90 O Atom 1487 CE2 TYR A 464 42.938 36.648 36.218 1.00 91.12 C Atom 1488 CD2 TYR A 464 43.918 37.436 36.798 1.00 88.77 C Atom 1489 C TYR A 464 47.764 39.872 36.869 1.00 76.02 C Atom 1490 O TYR A 464 47.512 40.845 36.161 1.00 76.26 O Atom 1491 N ILE A 465 48.396 39.975 38.034 1.00 78.43 N Atom 1492 CA ILE A 465 48.665 41.280 38.627 1.00 80.29 C Atom 1493 CB ILE A 465 48.992 41.182 40.144 1.00 81.97 C Atom 1494 CG1 ILE A 465 50.484 41.372 40.401 1.00 83.13 C Atom 1495 CD1 ILE A 465 50.842 42.799 40.715 1.00 92.35 C Atom 1496 CG2 ILE A 465 48.471 39.878 40.741 1.00 78.41 C Atom 1497 C ILE A 465 49.768 42.022 37.874 1.00 76.59 C Atom 1498 O ILE A 465 49.823 43.252 37.901 1.00 77.44 O Atom 1499 N ASN A 466 50.638 41.278 37.196 1.00 78.36 N Atom 1500 CA ASN A 466 51.640 41.897 36.333 1.00 76.20 C Atom 1501 CB ASN A 466 52.763 40.919 35.988 1.00 74.81 C Atom 1502 CG ASN A 466 53.939 41.022 36.940 1.00 76.72 C Atom 1503 OD1 ASN A 466 54.469 42.108 37.177 1.00 77.55 O Atom 1504 ND2 ASN A 466 54.361 39.887 37.483 1.00 73.99 N Atom 1505 C ASN A 466 51.012 42.457 35.063 1.00 75.91 C Atom 1506 O ASN A 466 51.301 43.584 34.665 1.00 81.44 O Atom 1507 N THR A 467 50.154 41.665 34.428 1.00 75.28 N Atom 1508 CA THR A 467 49.377 42.155 33.299 1.00 76.96 C Atom 1509 CB THR A 467 48.381 41.096 32.801 1.00 76.48 C Atom 1510 OG1 THR A 467 49.096 39.980 32.254 1.00 74.81 O Atom 1511 CG2 THR A 467 47.470 41.683 31.734 1.00 73.45 C Atom 1512 C THR A 467 48.605 43.399 33.718 1.00 76.56 C Atom 1513 O THR A 467 48.672 44.437 33.063 1.00 79.67 O Atom 1514 N ALA A 468 47.878 43.281 34.824 1.00 74.96 N Atom 1515 CA ALA A 468 47.094 44.385 35.361 1.00 76.83 C Atom 1516 CB ALA A 468 46.416 43.969 36.658 1.00 68.74 C Atom 1517 C ALA A 468 47.951 45.627 35.584 1.00 80.75 C Atom 1518 O ALA A 468 47.589 46.726 35.164 1.00 80.95 O Atom 1519 N LEU A 469 49.089 45.448 36.245 1.00 81.54 N Atom 1520 CA LEU A 469 49.973 46.565 36.556 1.00 82.38 C Atom 1521 CB LEU A 469 51.137 46.103 37.435 1.00 81.87 C Atom 1522 CG LEU A 469 52.023 47.205 38.019 1.00 81.01 C Atom 1523 CD1 LEU A 469 51.183 48.198 38.794 1.00 80.93 C Atom 1524 CD2 LEU A 469 53.106 46.612 38.906 1.00 86.50 C Atom 1525 C LEU A 469 50.498 47.231 35.287 1.00 85.00 C Atom 1526 O LEU A 469 50.642 48.452 35.231 1.00 86.43 O Atom 1527 N LEU A 470 50.779 46.424 34.268 1.00 85.45 N Atom 1528 CA LEU A 470 51.264 46.946 32.995 1.00 85.47 C Atom 1529 CB LEU A 470 51.644 45.803 32.053 1.00 89.13 C Atom 1530 CG LEU A 470 52.336 46.212 30.750 1.00 88.68 C Atom 1531 CD1 LEU A 470 53.587 47.020 31.043 1.00 84.79 C Atom 1532 CD2 LEU A 470 52.668 44.990 29.906 1.00 85.35 C Atom 1533 C LEU A 470 50.215 47.839 32.340 1.00 88.25 C Atom 1534 O LEU A 470 50.495 48.987 31.995 1.00 88.93 O Atom 1535 N ASN A 471 49.008 47.305 32.175 1.00 86.65 N Atom 1536 CA ASN A 471 47.903 48.066 31.604 1.00 83.96 C Atom 1537 CB ASN A 471 46.601 47.269 31.688 1.00 83.95 C Atom 1538 CG ASN A 471 46.620 46.030 30.818 1.00 96.73 C Atom 1539 OD1 ASN A 471 47.061 46.071 29.669 1.00 96.91 O Atom 1540 ND2 ASN A 471 46.132 44.918 31.359 1.00 96.89 N Atom 1541 C ASN A 471 47.733 49.410 32.297 1.00 86.92 C Atom 1542 O ASN A 471 47.733 50.456 31.651 1.00 93.36 O Atom 1543 N ALA A 472 47.592 49.373 33.618 1.00 83.65 N Atom 1544 CA ALA A 472 47.419 50.590 34.401 1.00 87.96 C Atom 1545 CB ALA A 472 47.261 50.251 35.876 1.00 86.96 C Atom 1546 C ALA A 472 48.581 51.557 34.196 1.00 91.60 C Atom 1547 O ALA A 472 48.390 52.771 34.163 1.00 87.38 O Atom 1548 N SER A 473 49.784 51.009 34.056 1.00 93.59 N Atom 1549 CA SER A 473 50.981 51.821 33.863 1.00 92.42 C Atom 1550 CB SER A 473 52.237 50.951 33.926 1.00 90.26 C Atom 1551 OG SER A 473 52.523 50.578 35.261 1.00 92.92 O Atom 1552 C SER A 473 50.948 52.592 32.549 1.00 98.96 C Atom 1553 O SER A 473 51.544 53.665 32.434 1.00 96.03 O Atom 1554 N CYS A 474 50.250 52.042 31.561 1.00 99.37 N Atom 1555 CA CYS A 474 50.136 52.685 30.259 1.00 101.03 C Atom 1556 CB CYS A 474 50.178 51.641 29.141 1.00 101.43 C Atom 1557 SG CYS A 474 51.761 50.785 28.980 1.00 105.38 S Atom 1558 C CYS A 474 48.871 53.529 30.145 1.00 103.44 C Atom 1559 O CYS A 474 48.914 54.663 29.674 1.00 110.09 O Atom 1560 N ALA A 475 47.746 52.974 30.585 1.00 92.77 N Atom 1561 CA ALA A 475 46.458 53.652 30.462 1.00 90.44 C Atom 1562 CB ALA A 475 45.315 52.681 30.730 1.00 86.92 C Atom 1563 C ALA A 475 46.337 54.875 31.372 1.00 98.34 C Atom 1564 O ALA A 475 45.409 55.672 31.227 1.00 109.54 O Atom 1565 N ALA A 476 47.271 55.024 32.304 1.00 91.84 N Atom 1566 CA ALA A 476 47.233 56.144 33.239 1.00 97.06 C Atom 1567 CB ALA A 476 47.128 55.634 34.672 1.00 95.53 C Atom 1568 C ALA A 476 48.442 57.059 33.082 1.00 106.08 C Atom 1569 O ALA A 476 48.347 58.131 32.489 1.00 114.77 O Atom 1570 N MET A 477 49.574 56.623 33.626 1.00 104.39 N Atom 1571 CA MET A 477 50.829 57.368 33.551 1.00 103.80 C Atom 1572 CB MET A 477 51.127 57.816 32.116 1.00 102.32 C Atom 1573 CG MET A 477 51.516 56.690 31.174 1.00 111.25 C Atom 1574 SD MET A 477 52.488 57.285 29.774 1.00 124.71 S Atom 1575 CE MET A 477 52.579 55.804 28.771 1.00 109.86 C Atom 1576 C MET A 477 50.889 58.565 34.498 1.00 97.55 C Atom 1577 O MET A 477 51.957 58.908 35.001 1.00 101.19 O Atom 1578 N ASP A 478 49.749 59.200 34.739 1.00 95.02 N Atom 1579 CA ASP A 478 49.716 60.389 35.586 1.00 102.85 C Atom 1580 CB ASP A 478 49.282 61.614 34.775 1.00 107.29 C Atom 1581 CG ASP A 478 49.603 62.924 35.477 1.00 110.52 C Atom 1582 OD1 ASP A 478 50.752 63.082 35.946 1.00 99.78 O Atom 1583 OD2 ASP A 478 48.707 63.793 35.557 1.00 107.84 O Atom 1584 C ASP A 478 48.800 60.210 36.795 1.00 103.37 C Atom 1585 O ASP A 478 48.592 61.143 37.571 1.00 101.37 O Atom 1586 N ASP A 479 48.259 59.007 36.955 1.00 106.13 N Atom 1587 CA ASP A 479 47.304 58.738 38.025 1.00 101.76 C Atom 1588 CB ASP A 479 45.983 58.247 37.432 1.00 105.34 C Atom 1589 CG ASP A 479 45.260 59.326 36.648 1.00 113.34 C Atom 1590 OD1 ASP A 479 44.688 60.241 37.283 1.00 112.05 O Atom 1591 OD2 ASP A 479 45.257 59.255 35.400 1.00 110.08 O Atom 1592 C ASP A 479 47.817 57.722 39.042 1.00 95.32 C Atom 1593 O ASP A 479 48.618 56.845 38.712 1.00 90.46 O Atom 1594 N PHE A 480 47.354 57.852 40.282 1.00 97.20 N Atom 1595 CA PHE A 480 47.581 56.828 41.292 1.00 89.73 C Atom 1596 CB PHE A 480 47.624 57.429 42.698 1.00 84.55 C Atom 1597 CG PHE A 480 48.804 58.316 42.948 1.00 77.93 C Atom 1598 CD1 PHE A 480 49.834 58.401 42.029 1.00 83.67 C Atom 1599 CE1 PHE A 480 50.927 59.216 42.267 1.00 86.33 C Atom 1600 CZ PHE A 480 51.002 59.944 43.440 1.00 80.66 C Atom 1601 CE2 PHE A 480 49.986 59.858 44.367 1.00 81.92 C Atom 1602 CD2 PHE A 480 48.897 59.044 44.123 1.00 77.53 C Atom 1603 C PHE A 480 46.442 55.824 41.211 1.00 88.58 C Atom 1604 O PHE A 480 45.383 56.032 41.797 1.00 90.46 O Atom 1605 N GLN A 481 46.661 54.738 40.481 1.00 86.33 N Atom 1606 CA GLN A 481 45.602 53.774 40.223 1.00 90.84 C Atom 1607 CB GLN A 481 45.807 53.125 38.854 1.00 94.71 C Atom 1608 CG GLN A 481 44.547 53.032 38.015 1.00 94.16 C Atom 1609 CD GLN A 481 44.098 54.383 37.489 1.00 104.11 C Atom 1610 OE1 GLN A 481 44.823 55.374 37.586 1.00 102.26 O Atom 1611 NE2 GLN A 481 42.896 54.428 36.924 1.00 108.23 N Atom 1612 C GLN A 481 45.526 52.706 41.312 1.00 89.03 C Atom 1613 O GLN A 481 46.547 52.271 41.845 1.00 81.80 O Atom 1614 N LEU A 482 44.305 52.293 41.641 1.00 86.45 N Atom 1615 CA LEU A 482 44.082 51.235 42.622 1.00 78.21 C Atom 1616 CB LEU A 482 42.894 51.582 43.520 1.00 72.62 C Atom 1617 CG LEU A 482 42.538 50.577 44.617 1.00 75.35 C Atom 1618 CD1 LEU A 482 43.610 50.533 45.700 1.00 70.68 C Atom 1619 CD2 LEU A 482 41.180 50.907 45.217 1.00 69.67 C Atom 1620 C LEU A 482 43.827 49.908 41.915 1.00 78.34 C Atom 1621 O LEU A 482 42.756 49.694 41.354 1.00 78.12 O Atom 1622 N ILE A 483 44.813 49.018 41.943 1.00 72.84 N Atom 1623 CA ILE A 483 44.700 47.743 41.244 1.00 71.52 C Atom 1624 CB ILE A 483 45.961 47.429 40.414 1.00 72.13 C Atom 1625 CG1 ILE A 483 46.178 48.486 39.330 1.00 72.91 C Atom 1626 CD1 ILE A 483 46.868 49.735 39.824 1.00 78.59 C Atom 1627 CG2 ILE A 483 45.855 46.046 39.789 1.00 73.99 C Atom 1628 C ILE A 483 44.460 46.583 42.202 1.00 72.14 C Atom 1629 O ILE A 483 45.309 46.276 43.037 1.00 73.78 O Atom 1630 N PRO A 484 43.294 45.933 42.085 1.00 70.37 N Atom 1631 CA PRO A 484 43.029 44.726 42.870 1.00 71.49 C Atom 1632 CB PRO A 484 41.589 44.364 42.483 1.00 69.80 C Atom 1633 CG PRO A 484 40.994 45.632 41.976 1.00 71.41 C Atom 1634 CD PRO A 484 42.119 46.358 41.306 1.00 74.99 C Atom 1635 C PRO A 484 43.972 43.600 42.465 1.00 70.09 C Atom 1636 O PRO A 484 44.237 43.422 41.276 1.00 67.19 O Atom 1637 N MET A 485 44.482 42.864 43.447 1.00 67.59 N Atom 1638 CA MET A 485 45.267 41.667 43.185 1.00 63.90 C Atom 1639 CB MET A 485 46.285 41.435 44.301 1.00 66.48 C Atom 1640 CG MET A 485 47.606 42.153 44.090 1.00 70.16 C Atom 1641 SD MET A 485 48.714 41.947 45.490 1.00 77.95 S Atom 1642 CE MET A 485 47.953 43.072 46.646 1.00 63.97 C Atom 1643 C MET A 485 44.330 40.473 43.064 1.00 65.36 C Atom 1644 O MET A 485 43.767 40.013 44.056 1.00 66.63 O Atom 1645 N ILE A 486 44.163 39.974 41.845 1.00 64.87 N Atom 1646 CA ILE A 486 43.154 38.957 41.577 1.00 66.04 C Atom 1647 CB ILE A 486 42.018 39.538 40.709 1.00 63.95 C Atom 1648 CG1 ILE A 486 41.306 40.657 41.464 1.00 64.74 C Atom 1649 CD1 ILE A 486 40.262 41.358 40.648 1.00 77.14 C Atom 1650 CG2 ILE A 486 41.023 38.459 40.312 1.00 69.76 C Atom 1651 C ILE A 486 43.722 37.716 40.899 1.00 68.18 C Atom 1652 O ILE A 486 44.679 37.797 40.132 1.00 71.59 O Atom 1653 N SER A 487 43.126 36.566 41.202 1.00 69.23 N Atom 1654 CA SER A 487 43.437 35.320 40.513 1.00 73.86 C Atom 1655 CB SER A 487 44.514 34.531 41.260 1.00 67.82 C Atom 1656 OG SER A 487 44.014 33.992 42.471 1.00 63.93 O Atom 1657 C SER A 487 42.165 34.490 40.382 1.00 73.36 C Atom 1658 O SER A 487 41.229 34.647 41.167 1.00 70.76 O Atom 1659 N LYS A 488 42.130 33.623 39.376 1.00 76.52 N Atom 1660 CA LYS A 488 40.981 32.754 39.141 1.00 72.72 C Atom 1661 CB LYS A 488 40.462 32.928 37.712 1.00 72.90 C Atom 1662 CG LYS A 488 40.041 34.346 37.352 1.00 81.08 C Atom 1663 CD LYS A 488 38.629 34.652 37.819 1.00 81.17 C Atom 1664 CE LYS A 488 38.212 36.055 37.402 1.00 89.05 C Atom 1665 NZ LYS A 488 38.297 36.248 35.927 1.00 92.54 N Atom 1666 C LYS A 488 41.384 31.303 39.358 1.00 71.50 C Atom 1667 O LYS A 488 42.547 30.943 39.174 1.00 78.04 O Atom 1668 N CYS A 489 40.429 30.468 39.746 1.00 74.31 N Atom 1669 CA CYS A 489 40.707 29.045 39.886 1.00 76.60 C Atom 1670 CB CYS A 489 41.487 28.761 41.173 1.00 67.44 C Atom 1671 SG CYS A 489 40.526 28.910 42.690 1.00 68.45 S Atom 1672 C CYS A 489 39.442 28.197 39.826 1.00 85.80 C Atom 1673 O CYS A 489 38.326 28.714 39.888 1.00 87.09 O Atom 1674 N ARG A 490 39.639 26.889 39.704 1.00 83.19 N Atom 1675 CA ARG A 490 38.548 25.934 39.591 1.00 85.93 C Atom 1676 CB ARG A 490 38.702 25.142 38.293 1.00 101.10 C Atom 1677 CG ARG A 490 37.414 24.612 37.689 1.00 104.63 C Atom 1678 CD ARG A 490 37.686 23.982 36.324 1.00 122.93 C Atom 1679 NE ARG A 490 38.036 24.980 35.313 1.00 136.22 N Atom 1680 CZ ARG A 490 39.277 25.351 35.012 1.00 137.63 C Atom 1681 NH1 ARG A 490 40.308 24.806 35.643 1.00 120.49 N Atom 1682 NH2 ARG A 490 39.484 26.269 34.077 1.00 132.28 N Atom 1683 C ARG A 490 38.607 24.991 40.789 1.00 88.07 C Atom 1684 O ARG A 490 39.622 24.332 41.016 1.00 87.75 O Atom 1685 N THR A 491 37.529 24.935 41.564 1.00 86.96 N Atom 1686 CA THR A 491 37.508 24.116 42.774 1.00 93.68 C Atom 1687 CB THR A 491 36.331 24.493 43.693 1.00 95.63 C Atom 1688 OG1 THR A 491 35.102 24.033 43.118 1.00 98.58 O Atom 1689 CG2 THR A 491 36.267 25.998 43.882 1.00 89.81 C Atom 1690 C THR A 491 37.435 22.624 42.457 1.00 96.81 C Atom 1691 O THR A 491 37.220 22.235 41.309 1.00 97.90 O Atom 1692 N LYS A 492 37.624 21.797 43.482 1.00 100.37 N Atom 1693 CA LYS A 492 37.486 20.355 43.339 1.00 102.80 C Atom 1694 CB LYS A 492 37.636 19.668 44.697 1.00 103.43 C Atom 1695 CG LYS A 492 38.610 20.337 45.648 1.00 109.13 C Atom 1696 CD LYS A 492 38.242 20.041 47.096 1.00 109.80 C Atom 1697 CE LYS A 492 38.191 18.544 47.366 1.00 109.10 C Atom 1698 NZ LYS A 492 39.545 17.926 47.286 1.00 109.13 N Atom 1699 C LYS A 492 36.102 20.056 42.794 1.00 108.46 C Atom 1700 O LYS A 492 35.941 19.297 41.839 1.00 105.73 O Atom 1701 N GLU A 493 35.102 20.667 43.421 1.00 108.53 N Atom 1702 CA GLU A 493 33.705 20.450 43.064 1.00 106.03 C Atom 1703 CB GLU A 493 32.782 21.128 44.081 1.00 110.39 C Atom 1704 CG GLU A 493 31.318 20.731 43.966 1.00 131.11 C Atom 1705 CD GLU A 493 31.067 19.276 44.329 1.00 139.93 C Atom 1706 OE1 GLU A 493 32.034 18.568 44.692 1.00 133.64 O Atom 1707 OE2 GLU A 493 29.896 18.843 44.249 1.00 137.52 O Atom 1708 C GLU A 493 33.394 20.948 41.654 1.00 106.78 C Atom 1709 O GLU A 493 32.409 20.528 41.045 1.00 117.05 O Atom 1710 N GLY A 494 34.229 21.850 41.144 1.00 100.48 N Atom 1711 CA GLY A 494 34.103 22.315 39.773 1.00 96.07 C Atom 1712 C GLY A 494 33.758 23.786 39.613 1.00 100.38 C Atom 1713 O GLY A 494 33.853 24.331 38.513 1.00 94.40 O Atom 1714 N ARG A 495 33.359 24.428 40.707 1.00 98.93 N Atom 1715 CA ARG A 495 32.953 25.832 40.674 1.00 100.52 C Atom 1716 CB ARG A 495 32.420 26.265 42.042 1.00 106.85 C Atom 1717 CG ARG A 495 31.308 25.388 42.610 1.00 118.96 C Atom 1718 CD ARG A 495 29.937 25.789 42.080 1.00 127.94 C Atom 1719 NE ARG A 495 29.678 25.265 40.741 1.00 135.43 N Atom 1720 CZ ARG A 495 29.048 24.120 40.493 1.00 134.93 C Atom 1721 NH1 ARG A 495 28.609 23.371 41.495 1.00 137.12 N Atom 1722 NH2 ARG A 495 28.857 23.725 39.242 1.00 128.91 N Atom 1723 C ARG A 495 34.114 26.741 40.280 1.00 95.96 C Atom 1724 O ARG A 495 35.260 26.497 40.664 1.00 93.44 O Atom 1725 N ARG A 496 33.817 27.787 39.514 1.00 87.69 N Atom 1726 CA ARG A 496 34.816 28.800 39.188 1.00 88.28 C Atom 1727 CB ARG A 496 34.518 29.455 37.837 1.00 98.02 C Atom 1728 CG ARG A 496 35.052 28.661 36.658 1.00 113.02 C Atom 1729 CD ARG A 496 34.888 29.395 35.336 1.00 123.36 C Atom 1730 NE ARG A 496 35.868 28.936 34.354 1.00 137.22 N Atom 1731 CZ ARG A 496 35.862 27.730 33.795 1.00 136.46 C Atom 1732 NH1 ARG A 496 34.925 26.850 34.119 1.00 131.65 N Atom 1733 NH2 ARG A 496 36.798 27.402 32.912 1.00 138.54 N Atom 1734 C ARG A 496 34.903 29.851 40.290 1.00 89.44 C Atom 1735 O ARG A 496 33.884 30.358 40.757 1.00 87.52 O Atom 1736 N LYS A 497 36.124 30.175 40.702 1.00 86.66 N Atom 1737 CA LYS A 497 36.332 31.093 41.814 1.00 81.09 C Atom 1738 CB LYS A 497 36.961 30.356 42.993 1.00 82.71 C Atom 1739 CG LYS A 497 35.969 29.830 44.009 1.00 88.26 C Atom 1740 CD LYS A 497 36.698 29.202 45.191 1.00 94.51 C Atom 1741 CE LYS A 497 37.929 30.020 45.582 1.00 89.73 C Atom 1742 NZ LYS A 497 38.654 29.442 46.749 1.00 81.73 N Atom 1743 C LYS A 497 37.202 32.287 41.451 1.00 81.56 C Atom 1744 O LYS A 497 38.178 32.155 40.716 1.00 84.13 O Atom 1745 N THR A 498 36.842 33.449 41.985 1.00 75.23 N Atom 1746 CA THR A 498 37.639 34.656 41.829 1.00 71.23 C Atom 1747 CB THR A 498 36.807 35.810 41.253 1.00 72.82 C Atom 1748 OG1 THR A 498 36.430 35.502 39.906 1.00 77.86 O Atom 1749 CG2 THR A 498 37.606 37.105 41.272 1.00 71.33 C Atom 1750 C THR A 498 38.205 35.068 43.182 1.00 74.26 C Atom 1751 O THR A 498 37.460 35.288 44.136 1.00 75.34 O Atom 1752 N ASN A 499 39.527 35.172 43.257 1.00 70.67 N Atom 1753 CA ASN A 499 40.206 35.447 44.514 1.00 63.91 C Atom 1754 CB ASN A 499 41.331 34.435 44.716 1.00 65.39 C Atom 1755 CG ASN A 499 40.891 33.014 44.423 1.00 68.37 C Atom 1756 OD1 ASN A 499 40.049 32.456 45.126 1.00 71.85 O Atom 1757 ND2 ASN A 499 41.464 32.420 43.381 1.00 65.34 N Atom 1758 C ASN A 499 40.772 36.859 44.584 1.00 65.38 C Atom 1759 O ASN A 499 41.314 37.365 43.603 1.00 69.00 O Atom 1760 N LEU A 500 40.640 37.491 45.747 1.00 63.20 N Atom 1761 CA LEU A 500 41.254 38.794 45.994 1.00 60.37 C Atom 1762 CB LEU A 500 40.208 39.825 46.427 1.00 60.77 C Atom 1763 CG LEU A 500 40.737 41.241 46.697 1.00 63.98 C Atom 1764 CD1 LEU A 500 41.074 41.959 45.394 1.00 61.84 C Atom 1765 CD2 LEU A 500 39.742 42.055 47.512 1.00 58.86 C Atom 1766 C LEU A 500 42.327 38.671 47.070 1.00 59.67 C Atom 1767 O LEU A 500 42.035 38.283 48.201 1.00 58.67 O Atom 1768 N TYR A 501 43.564 39.007 46.718 1.00 61.16 N Atom 1769 CA TYR A 501 44.682 38.914 47.650 1.00 55.17 C Atom 1770 CB TYR A 501 45.960 38.572 46.896 1.00 56.38 C Atom 1771 CG TYR A 501 45.953 37.225 46.223 1.00 58.00 C Atom 1772 CD1 TYR A 501 46.320 36.082 46.913 1.00 50.62 C Atom 1773 CE1 TYR A 501 46.327 34.851 46.297 1.00 53.18 C Atom 1774 CZ TYR A 501 45.959 34.749 44.972 1.00 57.04 C Atom 1775 OH TYR A 501 45.961 33.524 44.353 1.00 64.49 O Atom 1776 CE2 TYR A 501 45.591 35.868 44.264 1.00 58.92 C Atom 1777 CD2 TYR A 501 45.590 37.098 44.891 1.00 61.07 C Atom 1778 C TYR A 501 44.904 40.210 48.414 1.00 58.54 C Atom 1779 O TYR A 501 45.502 40.214 49.489 1.00 55.59 O Atom 1780 N GLY A 502 44.424 41.306 47.840 1.00 58.69 N Atom 1781 CA GLY A 502 44.635 42.627 48.392 1.00 56.68 C Atom 1782 C GLY A 502 44.694 43.620 47.253 1.00 60.79 C Atom 1783 O GLY A 502 44.205 43.339 46.162 1.00 65.65 O Atom 1784 N PHE A 503 45.305 44.774 47.499 1.00 66.18 N Atom 1785 CA PHE A 503 45.384 45.822 46.490 1.00 66.77 C Atom 1786 CB PHE A 503 44.504 47.011 46.880 1.00 62.72 C Atom 1787 CG PHE A 503 43.038 46.691 46.911 1.00 73.86 C Atom 1788 CD1 PHE A 503 42.443 46.213 48.067 1.00 70.23 C Atom 1789 CE1 PHE A 503 41.098 45.917 48.096 1.00 65.87 C Atom 1790 CZ PHE A 503 40.329 46.093 46.964 1.00 69.17 C Atom 1791 CE2 PHE A 503 40.910 46.565 45.806 1.00 69.73 C Atom 1792 CD2 PHE A 503 42.256 46.861 45.782 1.00 67.96 C Atom 1793 C PHE A 503 46.806 46.301 46.236 1.00 67.47 C Atom 1794 O PHE A 503 47.692 46.166 47.081 1.00 64.76 O Atom 1795 N ILE A 504 47.008 46.856 45.050 1.00 69.14 N Atom 1796 CA ILE A 504 48.251 47.527 44.716 1.00 71.12 C Atom 1797 CB ILE A 504 49.055 46.761 43.654 1.00 66.33 C Atom 1798 CG1 ILE A 504 49.603 45.458 44.241 1.00 74.06 C Atom 1799 CD1 ILE A 504 50.740 44.852 43.444 1.00 70.02 C Atom 1800 CG2 ILE A 504 50.194 47.615 43.140 1.00 69.94 C Atom 1801 C ILE A 504 47.929 48.921 44.206 1.00 74.99 C Atom 1802 O ILE A 504 47.016 49.103 43.404 1.00 70.71 O Atom 1803 N ILE A 505 48.675 49.905 44.692 1.00 75.11 N Atom 1804 CA ILE A 505 48.500 51.281 44.256 1.00 74.63 C Atom 1805 CB ILE A 505 48.408 52.245 45.451 1.00 74.23 C Atom 1806 CG1 ILE A 505 47.268 51.819 46.382 1.00 74.58 C Atom 1807 CD1 ILE A 505 47.135 52.673 47.628 1.00 73.13 C Atom 1808 CG2 ILE A 505 48.208 53.672 44.966 1.00 68.69 C Atom 1809 C ILE A 505 49.648 51.692 43.343 1.00 76.98 C Atom 1810 O ILE A 505 50.806 51.723 43.759 1.00 74.69 O Atom 1811 N LYS A 506 49.317 51.993 42.092 1.00 80.75 N Atom 1812 CA LYS A 506 50.317 52.360 41.101 1.00 79.40 C Atom 1813 CB LYS A 506 49.777 52.133 39.688 1.00 80.06 C Atom 1814 CG LYS A 506 50.772 52.455 38.584 1.00 84.34 C Atom 1815 CD LYS A 506 50.097 52.471 37.222 1.00 90.24 C Atom 1816 CE LYS A 506 49.160 53.663 37.082 1.00 91.70 C Atom 1817 NZ LYS A 506 49.897 54.961 37.048 1.00 87.41 N Atom 1818 C LYS A 506 50.744 53.812 41.263 1.00 85.31 C Atom 1819 O LYS A 506 49.913 54.690 41.497 1.00 85.19 O Atom 1820 N GLY A 507 52.045 54.054 41.140 1.00 84.45 N Atom 1821 CA GLY A 507 52.582 55.400 41.198 1.00 88.58 C Atom 1822 C GLY A 507 52.453 56.090 39.855 1.00 99.97 C Atom 1823 O GLY A 507 51.719 55.624 38.982 1.00 96.65 O Atom 1824 N ARG A 508 53.169 57.199 39.686 1.00 98.69 N Atom 1825 CA ARG A 508 53.101 57.974 38.449 1.00 99.18 C Atom 1826 CB ARG A 508 54.206 59.032 38.406 1.00 111.68 C Atom 1827 CG ARG A 508 53.791 60.349 39.027 1.00 116.27 C Atom 1828 CD ARG A 508 52.581 60.909 38.304 1.00 106.41 C Atom 1829 NE ARG A 508 51.813 61.828 39.137 1.00 111.22 N Atom 1830 CZ ARG A 508 52.042 63.133 39.218 1.00 119.60 C Atom 1831 NH1 ARG A 508 53.025 63.677 38.515 1.00 117.51 N Atom 1832 NH2 ARG A 508 51.289 63.891 40.004 1.00 112.39 N Atom 1833 C ARG A 508 53.140 57.103 37.195 1.00 101.22 C Atom 1834 O ARG A 508 52.133 56.956 36.507 1.00 108.96 O Atom 1835 N SER A 509 54.304 56.530 36.908 1.00 94.36 N Atom 1836 CA SER A 509 54.479 55.634 35.762 1.00 99.65 C Atom 1837 CB SER A 509 53.408 54.533 35.740 1.00 97.35 C Atom 1838 OG SER A 509 52.232 54.945 35.066 1.00 88.11 O Atom 1839 C SER A 509 54.536 56.358 34.411 1.00 111.15 C Atom 1840 O SER A 509 53.931 55.915 33.433 1.00 108.69 O Atom 1841 N HIS A 510 55.264 57.470 34.365 1.00 113.42 N Atom 1842 CA HIS A 510 55.594 58.121 33.103 1.00 109.30 C Atom 1843 CB HIS A 510 55.638 59.642 33.269 1.00 110.50 C Atom 1844 CG HIS A 510 54.296 60.302 33.208 1.00 109.11 C Atom 1845 ND1 HIS A 510 53.786 61.052 34.246 1.00 103.79 N Atom 1846 CE1 HIS A 510 52.596 61.513 33.910 1.00 103.24 C Atom 1847 NE2 HIS A 510 52.313 61.090 32.690 1.00 103.00 N Atom 1848 CD2 HIS A 510 53.363 60.333 32.228 1.00 107.00 C Atom 1849 C HIS A 510 56.968 57.628 32.670 1.00 119.53 C Atom 1850 O HIS A 510 57.862 57.509 33.505 1.00 130.77 O Atom 1851 N LEU A 511 57.117 57.328 31.380 1.00 124.12 N Atom 1852 CA LEU A 511 58.422 57.056 30.747 1.00 137.93 C Atom 1853 CB LEU A 511 59.593 57.155 31.735 1.00 137.46 C Atom 1854 CG LEU A 511 60.123 58.589 31.901 1.00 138.60 C Atom 1855 CD1 LEU A 511 60.683 58.842 33.298 1.00 135.92 C Atom 1856 CD2 LEU A 511 61.142 58.953 30.815 1.00 125.68 C Atom 1857 C LEU A 511 58.481 55.757 29.945 1.00 131.30 C Atom 1858 O LEU A 511 58.098 54.695 30.432 1.00 126.45 O Atom 1859 N ARG A 512 58.973 55.873 28.712 1.00 137.39 N Atom 1860 CA ARG A 512 59.056 54.764 27.763 1.00 140.96 C Atom 1861 CB ARG A 512 58.626 55.241 26.371 1.00 140.33 C Atom 1862 CG ARG A 512 58.493 54.140 25.325 1.00 139.62 C Atom 1863 CD ARG A 512 57.131 53.468 25.393 1.00 143.22 C Atom 1864 NE ARG A 512 56.045 54.408 25.132 1.00 141.86 N Atom 1865 CZ ARG A 512 55.310 54.985 26.076 1.00 134.24 C Atom 1866 NH1 ARG A 512 55.535 54.716 27.355 1.00 134.73 N Atom 1867 NH2 ARG A 512 54.345 55.830 25.742 1.00 134.39 N Atom 1868 C ARG A 512 60.484 54.232 27.694 1.00 139.50 C Atom 1869 O ARG A 512 61.070 54.132 26.615 1.00 142.92 O Atom 1870 N ASN A 513 61.043 53.893 28.850 1.00 135.46 N Atom 1871 CA ASN A 513 62.446 53.512 28.928 1.00 125.44 C Atom 1872 CB ASN A 513 63.130 54.245 30.085 1.00 132.43 C Atom 1873 CG ASN A 513 62.700 55.705 30.197 1.00 137.15 C Atom 1874 OD1 ASN A 513 62.826 56.316 31.259 1.00 136.52 O Atom 1875 ND2 ASN A 513 62.185 56.265 29.104 1.00 130.22 N Atom 1876 C ASN A 513 62.643 52.007 29.071 1.00 123.04 C Atom 1877 O ASN A 513 63.766 51.513 28.977 1.00 128.96 O Atom 1878 N ASP A 514 61.544 51.291 29.301 1.00 117.56 N Atom 1879 CA ASP A 514 61.555 49.829 29.426 1.00 112.59 C Atom 1880 CB ASP A 514 62.049 49.166 28.137 1.00 111.51 C Atom 1881 CG ASP A 514 60.911 48.714 27.241 1.00 118.40 C Atom 1882 OD1 ASP A 514 59.802 49.283 27.347 1.00 117.30 O Atom 1883 OD2 ASP A 514 61.127 47.786 26.433 1.00 119.26 O Atom 1884 C ASP A 514 62.333 49.289 30.626 1.00 104.14 C Atom 1885 O ASP A 514 62.024 48.212 31.138 1.00 98.36 O Atom 1886 N THR A 515 63.348 50.026 31.062 1.00 106.19 N Atom 1887 CA THR A 515 64.100 49.646 32.248 1.00 99.00 C Atom 1888 CB THR A 515 65.618 49.618 31.981 1.00 106.99 C Atom 1889 OG1 THR A 515 66.245 48.687 32.872 1.00 105.95 O Atom 1890 CG2 THR A 515 66.228 51.001 32.177 1.00 114.33 C Atom 1891 C THR A 515 63.794 50.621 33.378 1.00 103.41 C Atom 1892 O THR A 515 64.252 50.451 34.509 1.00 98.92 O Atom 1893 N ASP A 516 63.010 51.646 33.057 1.00 107.85 N Atom 1894 CA ASP A 516 62.617 52.655 34.032 1.00 106.88 C Atom 1895 CB ASP A 516 62.084 53.900 33.330 1.00 110.27 C Atom 1896 CG ASP A 516 62.067 55.113 34.232 1.00 115.15 C Atom 1897 OD1 ASP A 516 61.576 56.170 33.792 1.00 123.43 O Atom 1898 OD2 ASP A 516 62.544 55.009 35.381 1.00 107.06 O Atom 1899 C ASP A 516 61.550 52.087 34.951 1.00 96.40 C Atom 1900 O ASP A 516 60.759 51.234 34.541 1.00 93.26 O Atom 1901 N VAL A 517 61.523 52.570 36.189 1.00 91.04 N Atom 1902 CA VAL A 517 60.691 51.968 37.221 1.00 87.05 C Atom 1903 CB VAL A 517 61.497 51.719 38.516 1.00 87.89 C Atom 1904 CG1 VAL A 517 62.961 51.442 38.191 1.00 82.80 C Atom 1905 CG2 VAL A 517 61.376 52.903 39.459 1.00 85.95 C Atom 1906 C VAL A 517 59.451 52.786 37.570 1.00 84.67 C Atom 1907 O VAL A 517 59.472 54.018 37.559 1.00 89.22 O Atom 1908 N VAL A 518 58.369 52.078 37.875 1.00 89.01 N Atom 1909 CA VAL A 518 57.164 52.696 38.411 1.00 80.65 C Atom 1910 CB VAL A 518 55.914 52.291 37.614 1.00 76.06 C Atom 1911 CG1 VAL A 518 55.999 50.829 37.209 1.00 79.16 C Atom 1912 CG2 VAL A 518 54.657 52.555 38.430 1.00 82.91 C Atom 1913 C VAL A 518 56.988 52.272 39.865 1.00 77.38 C Atom 1914 O VAL A 518 56.908 51.080 40.167 1.00 79.78 O Atom 1915 N ASN A 519 56.943 53.247 40.765 1.00 81.60 N Atom 1916 CA ASN A 519 56.774 52.954 42.179 1.00 78.44 C Atom 1917 CB ASN A 519 57.139 54.171 43.028 1.00 82.35 C Atom 1918 CG ASN A 519 58.632 54.408 43.088 1.00 86.30 C Atom 1919 OD1 ASN A 519 59.090 55.549 43.154 1.00 100.25 O Atom 1920 ND2 ASN A 519 59.403 53.327 43.054 1.00 80.52 N Atom 1921 C ASN A 519 55.352 52.517 42.486 1.00 79.40 C Atom 1922 O ASN A 519 54.398 53.053 41.929 1.00 82.03 O Atom 1923 N PHE A 520 55.216 51.534 43.367 1.00 73.93 N Atom 1924 CA PHE A 520 53.902 51.095 43.814 1.00 72.38 C Atom 1925 CB PHE A 520 53.352 49.984 42.912 1.00 70.76 C Atom 1926 CG PHE A 520 54.041 48.655 43.087 1.00 74.02 C Atom 1927 CD1 PHE A 520 53.609 47.755 44.049 1.00 69.33 C Atom 1928 CE1 PHE A 520 54.240 46.533 44.213 1.00 71.47 C Atom 1929 CZ PHE A 520 55.310 46.196 43.407 1.00 72.46 C Atom 1930 CE2 PHE A 520 55.747 47.083 42.442 1.00 76.97 C Atom 1931 CD2 PHE A 520 55.114 48.304 42.286 1.00 75.06 C Atom 1932 C PHE A 520 53.963 50.624 45.260 1.00 70.47 C Atom 1933 O PHE A 520 55.023 50.247 45.760 1.00 68.64 O Atom 1934 N VAL A 521 52.818 50.666 45.929 1.00 70.67 N Atom 1935 CA VAL A 521 52.693 50.127 47.274 1.00 68.61 C Atom 1936 CB VAL A 521 52.253 51.209 48.286 1.00 64.45 C Atom 1937 CG1 VAL A 521 51.574 52.359 47.573 1.00 71.14 C Atom 1938 CG2 VAL A 521 51.355 50.616 49.364 1.00 59.16 C Atom 1939 C VAL A 521 51.708 48.970 47.249 1.00 62.15 C Atom 1940 O VAL A 521 50.626 49.074 46.671 1.00 60.72 O Atom 1941 N SER A 522 52.101 47.855 47.851 1.00 57.19 N Atom 1942 CA SER A 522 51.248 46.680 47.879 1.00 61.72 C Atom 1943 CB SER A 522 52.058 45.420 47.576 1.00 57.86 C Atom 1944 OG SER A 522 53.020 45.179 48.588 1.00 59.87 O Atom 1945 C SER A 522 50.559 46.547 49.231 1.00 59.21 C Atom 1946 O SER A 522 51.125 46.897 50.265 1.00 56.48 O Atom 1947 N MET A 523 49.330 46.042 49.208 1.00 54.51 N Atom 1948 CA MET A 523 48.546 45.832 50.419 1.00 56.87 C Atom 1949 CB MET A 523 47.485 46.924 50.554 1.00 58.52 C Atom 1950 CG MET A 523 48.057 48.323 50.725 1.00 58.94 C Atom 1951 SD MET A 523 46.849 49.621 50.394 1.00 69.59 S Atom 1952 CE MET A 523 47.596 50.997 51.260 1.00 76.50 C Atom 1953 C MET A 523 47.887 44.462 50.362 1.00 60.05 C Atom 1954 O MET A 523 46.898 44.273 49.658 1.00 62.36 O Atom 1955 N GLU A 524 48.436 43.506 51.105 1.00 55.73 N Atom 1956 CA GLU A 524 48.002 42.119 50.978 1.00 58.16 C Atom 1957 CB GLU A 524 49.154 41.268 50.447 1.00 53.42 C Atom 1958 CG GLU A 524 49.892 41.922 49.293 1.00 54.85 C Atom 1959 CD GLU A 524 51.053 41.092 48.794 1.00 56.83 C Atom 1960 OE1 GLU A 524 50.836 39.911 48.456 1.00 62.24 O Atom 1961 OE2 GLU A 524 52.180 41.622 48.728 1.00 62.43 O Atom 1962 C GLU A 524 47.452 41.529 52.277 1.00 58.45 C Atom 1963 O GLU A 524 48.033 41.706 53.345 1.00 54.88 O Atom 1964 N PHE A 525 46.327 40.826 52.173 1.00 60.13 N Atom 1965 CA PHE A 525 45.701 40.205 53.332 1.00 56.06 C Atom 1966 CB PHE A 525 44.286 39.725 52.996 1.00 55.75 C Atom 1967 CG PHE A 525 43.467 40.720 52.227 1.00 56.94 C Atom 1968 CD1 PHE A 525 43.335 42.022 52.674 1.00 57.98 C Atom 1969 CE1 PHE A 525 42.574 42.936 51.974 1.00 56.08 C Atom 1970 CZ PHE A 525 41.925 42.550 50.817 1.00 55.46 C Atom 1971 CE2 PHE A 525 42.041 41.249 50.364 1.00 54.62 C Atom 1972 CD2 PHE A 525 42.804 40.341 51.070 1.00 54.55 C Atom 1973 C PHE A 525 46.524 39.013 53.786 1.00 55.29 C Atom 1974 O PHE A 525 47.128 38.323 52.970 1.00 57.41 O Atom 1975 N SER A 526 46.534 38.766 55.090 1.00 54.58 N Atom 1976 CA SER A 526 47.236 37.617 55.650 1.00 55.31 C Atom 1977 CB SER A 526 48.750 37.869 55.679 1.00 54.88 C Atom 1978 OG SER A 526 49.450 36.813 56.324 1.00 51.24 O Atom 1979 C SER A 526 46.723 37.285 57.048 1.00 55.06 C Atom 1980 O SER A 526 46.322 38.169 57.801 1.00 56.18 O Atom 1981 N LEU A 527 46.727 35.999 57.376 1.00 51.02 N Atom 1982 CA LEU A 527 46.428 35.542 58.724 1.00 51.31 C Atom 1983 CB LEU A 527 45.720 34.189 58.681 1.00 53.47 C Atom 1984 CG LEU A 527 44.203 34.193 58.886 1.00 59.57 C Atom 1985 CD1 LEU A 527 43.532 35.413 58.262 1.00 51.38 C Atom 1986 CD2 LEU A 527 43.599 32.900 58.363 1.00 53.04 C Atom 1987 C LEU A 527 47.708 35.433 59.535 1.00 53.93 C Atom 1988 O LEU A 527 47.666 35.179 60.736 1.00 57.61 O Atom 1989 N THR A 528 48.843 35.634 58.872 1.00 54.42 N Atom 1990 CA THR A 528 50.144 35.460 59.508 1.00 57.39 C Atom 1991 CB THR A 528 51.268 35.263 58.470 1.00 55.86 C Atom 1992 OG1 THR A 528 51.009 34.087 57.694 1.00 62.06 O Atom 1993 CG2 THR A 528 52.611 35.116 59.164 1.00 49.02 C Atom 1994 C THR A 528 50.513 36.625 60.418 1.00 59.31 C Atom 1995 O THR A 528 50.564 37.774 59.983 1.00 59.82 O Atom 1996 N ASP A 529 50.766 36.320 61.685 1.00 57.53 N Atom 1997 CA ASP A 529 51.229 37.322 62.634 1.00 60.22 C Atom 1998 CB ASP A 529 51.086 36.797 64.064 1.00 62.79 C Atom 1999 CG ASP A 529 51.133 37.900 65.101 1.00 66.95 C Atom 2000 OD1 ASP A 529 51.669 38.989 64.804 1.00 63.33 O Atom 2001 OD2 ASP A 529 50.632 37.674 66.221 1.00 74.38 O Atom 2002 C ASP A 529 52.686 37.668 62.335 1.00 61.47 C Atom 2003 O ASP A 529 53.564 36.806 62.415 1.00 63.46 O Atom 2004 N PRO A 530 52.948 38.936 61.985 1.00 60.30 N Atom 2005 CA PRO A 530 54.291 39.372 61.579 1.00 58.30 C Atom 2006 CB PRO A 530 54.078 40.824 61.146 1.00 57.76 C Atom 2007 CG PRO A 530 52.821 41.256 61.818 1.00 59.76 C Atom 2008 CD PRO A 530 51.970 40.039 61.986 1.00 59.18 C Atom 2009 C PRO A 530 55.292 39.314 62.725 1.00 61.40 C Atom 2010 O PRO A 530 56.491 39.469 62.499 1.00 65.44 O Atom 2011 N ARG A 531 54.806 39.086 63.939 1.00 62.85 N Atom 2012 CA ARG A 531 55.671 39.104 65.113 1.00 60.29 C Atom 2013 CB ARG A 531 54.900 39.591 66.341 1.00 61.50 C Atom 2014 CG ARG A 531 54.659 41.089 66.338 1.00 61.64 C Atom 2015 CD ARG A 531 53.483 41.467 67.222 1.00 67.68 C Atom 2016 NE ARG A 531 52.265 40.783 66.800 1.00 73.85 N Atom 2017 CZ ARG A 531 51.053 41.034 67.283 1.00 67.01 C Atom 2018 NH1 ARG A 531 50.879 41.966 68.213 1.00 65.87 N Atom 2019 NH2 ARG A 531 50.010 40.352 66.831 1.00 64.69 N Atom 2020 C ARG A 531 56.344 37.765 65.396 1.00 64.45 C Atom 2021 O ARG A 531 57.273 37.695 66.201 1.00 69.93 O Atom 2022 N LEU A 532 55.876 36.708 64.737 1.00 65.93 N Atom 2023 CA LEU A 532 56.517 35.401 64.849 1.00 66.91 C Atom 2024 CB LEU A 532 55.698 34.325 64.135 1.00 68.50 C Atom 2025 CG LEU A 532 54.347 33.925 64.729 1.00 70.91 C Atom 2026 CD1 LEU A 532 53.694 32.854 63.871 1.00 68.78 C Atom 2027 CD2 LEU A 532 54.498 33.446 66.165 1.00 75.24 C Atom 2028 C LEU A 532 57.918 35.449 64.249 1.00 67.94 C Atom 2029 O LEU A 532 58.871 34.929 64.828 1.00 72.79 O Atom 2030 N GLU A 533 58.031 36.070 63.079 1.00 65.14 N Atom 2031 CA GLU A 533 59.310 36.206 62.391 1.00 60.89 C Atom 2032 CB GLU A 533 59.410 35.203 61.240 1.00 53.93 C Atom 2033 CG GLU A 533 59.428 33.749 61.677 1.00 53.23 C Atom 2034 CD GLU A 533 59.314 32.790 60.508 1.00 61.24 C Atom 2035 OE1 GLU A 533 58.592 33.115 59.542 1.00 68.42 O Atom 2036 OE2 GLU A 533 59.937 31.706 60.555 1.00 59.73 O Atom 2037 C GLU A 533 59.476 37.626 61.859 1.00 63.85 C Atom 2038 O GLU A 533 59.411 37.853 60.650 1.00 63.55 O Atom 2039 N PRO A 534 59.692 38.589 62.765 1.00 66.99 N Atom 2040 CA PRO A 534 59.811 39.996 62.372 1.00 59.40 C Atom 2041 CB PRO A 534 60.214 40.692 63.674 1.00 57.85 C Atom 2042 CG PRO A 534 59.765 39.778 64.756 1.00 60.32 C Atom 2043 CD PRO A 534 59.899 38.394 64.210 1.00 63.39 C Atom 2044 C PRO A 534 60.900 40.184 61.325 1.00 60.03 C Atom 2045 O PRO A 534 60.783 41.049 60.458 1.00 62.63 O Atom 2046 N HIS A 535 61.946 39.369 61.407 1.00 56.34 N Atom 2047 CA HIS A 535 63.078 39.491 60.498 1.00 57.85 C Atom 2048 CB HIS A 535 64.171 38.477 60.851 1.00 64.18 C Atom 2049 CG HIS A 535 63.703 37.056 60.865 1.00 62.94 C Atom 2050 ND1 HIS A 535 63.201 36.447 61.996 1.00 62.63 N Atom 2051 CE1 HIS A 535 62.878 35.197 61.714 1.00 61.37 C Atom 2052 NE2 HIS A 535 63.155 34.971 60.443 1.00 58.98 N Atom 2053 CD2 HIS A 535 63.676 36.117 59.889 1.00 61.58 C Atom 2054 C HIS A 535 62.655 39.331 59.042 1.00 60.72 C Atom 2055 O HIS A 535 63.177 40.010 58.156 1.00 62.17 O Atom 2056 N LYS A 536 61.705 38.433 58.807 1.00 62.78 N Atom 2057 CA LYS A 536 61.193 38.170 57.469 1.00 58.87 C Atom 2058 CB LYS A 536 60.228 36.981 57.507 1.00 60.83 C Atom 2059 CG LYS A 536 59.564 36.664 56.177 1.00 59.41 C Atom 2060 CD LYS A 536 58.722 35.403 56.270 1.00 55.04 C Atom 2061 CE LYS A 536 58.083 35.064 54.936 1.00 54.85 C Atom 2062 NZ LYS A 536 57.444 33.723 54.972 1.00 57.21 N Atom 2063 C LYS A 536 60.497 39.395 56.877 1.00 58.87 C Atom 2064 O LYS A 536 60.429 39.551 55.658 1.00 57.72 O Atom 2065 N TRP A 537 59.993 40.268 57.742 1.00 58.71 N Atom 2066 CA TRP A 537 59.160 41.383 57.296 1.00 62.05 C Atom 2067 CB TRP A 537 57.811 41.345 58.020 1.00 60.19 C Atom 2068 CG TRP A 537 57.185 39.987 58.001 1.00 59.14 C Atom 2069 CD1 TRP A 537 57.031 39.141 59.058 1.00 57.70 C Atom 2070 NE1 TRP A 537 56.423 37.979 58.651 1.00 56.73 N Atom 2071 CE2 TRP A 537 56.179 38.056 57.299 1.00 56.68 C Atom 2072 CD2 TRP A 537 56.651 39.309 56.864 1.00 55.69 C Atom 2073 CE3 TRP A 537 56.520 39.638 55.509 1.00 55.53 C Atom 2074 CZ3 TRP A 537 55.934 38.723 54.656 1.00 56.97 C Atom 2075 CH2 TRP A 537 55.475 37.488 55.124 1.00 55.53 C Atom 2076 CZ2 TRP A 537 55.589 37.134 56.442 1.00 58.32 C Atom 2077 C TRP A 537 59.809 42.755 57.472 1.00 63.96 C Atom 2078 O TRP A 537 59.117 43.743 57.716 1.00 63.29 O Atom 2079 N GLU A 538 61.130 42.817 57.334 1.00 65.96 N Atom 2080 CA GLU A 538 61.860 44.063 57.545 1.00 65.11 C Atom 2081 CB GLU A 538 63.367 43.843 57.392 1.00 63.72 C Atom 2082 CG GLU A 538 63.848 43.763 55.954 1.00 74.08 C Atom 2083 CD GLU A 538 65.357 43.655 55.848 1.00 83.85 C Atom 2084 OE1 GLU A 538 65.867 43.522 54.714 1.00 79.38 O Atom 2085 OE2 GLU A 538 66.032 43.703 56.897 1.00 90.45 O Atom 2086 C GLU A 538 61.400 45.169 56.597 1.00 63.75 C Atom 2087 O GLU A 538 61.392 46.347 56.964 1.00 68.13 O Atom 2088 N LYS A 539 61.009 44.788 55.383 1.00 61.11 N Atom 2089 CA LYS A 539 60.620 45.757 54.363 1.00 63.24 C Atom 2090 CB LYS A 539 60.858 45.183 52.963 1.00 62.50 C Atom 2091 CG LYS A 539 62.242 44.600 52.743 1.00 65.10 C Atom 2092 CD LYS A 539 62.432 44.191 51.287 1.00 67.07 C Atom 2093 CE LYS A 539 63.851 43.708 51.026 1.00 64.39 C Atom 2094 NZ LYS A 539 64.164 42.471 51.788 1.00 69.03 N Atom 2095 C LYS A 539 59.159 46.173 54.494 1.00 61.12 C Atom 2096 O LYS A 539 58.668 46.982 53.708 1.00 60.34 O Atom 2097 N TYR A 540 58.472 45.622 55.488 1.00 62.51 N Atom 2098 CA TYR A 540 57.027 45.787 55.597 1.00 61.10 C Atom 2099 CB TYR A 540 56.348 44.417 55.682 1.00 56.00 C Atom 2100 CG TYR A 540 56.346 43.623 54.399 1.00 57.52 C Atom 2101 CD1 TYR A 540 57.370 42.730 54.111 1.00 57.44 C Atom 2102 CE1 TYR A 540 57.370 41.994 52.939 1.00 53.53 C Atom 2103 CZ TYR A 540 56.333 42.146 52.042 1.00 58.19 C Atom 2104 OH TYR A 540 56.316 41.422 50.870 1.00 62.99 O Atom 2105 CE2 TYR A 540 55.304 43.023 52.310 1.00 58.41 C Atom 2106 CD2 TYR A 540 55.314 43.754 53.481 1.00 55.21 C Atom 2107 C TYR A 540 56.577 46.615 56.793 1.00 58.70 C Atom 2108 O TYR A 540 57.186 46.577 57.859 1.00 58.88 O Atom 2109 N CYS A 541 55.501 47.365 56.593 1.00 57.41 N Atom 2110 CA CYS A 541 54.694 47.855 57.699 1.00 59.92 C Atom 2111 CB CYS A 541 54.281 49.307 57.486 1.00 64.38 C Atom 2112 SG CYS A 541 53.137 49.915 58.744 1.00 60.15 S Atom 2113 C CYS A 541 53.454 46.979 57.735 1.00 57.68 C Atom 2114 O CYS A 541 52.736 46.882 56.743 1.00 58.34 O Atom 2115 N VAL A 542 53.206 46.322 58.862 1.00 57.96 N Atom 2116 CA VAL A 542 52.066 45.418 58.959 1.00 62.20 C Atom 2117 CB VAL A 542 52.490 44.014 59.434 1.00 59.73 C Atom 2118 CG1 VAL A 542 51.345 43.030 59.266 1.00 53.93 C Atom 2119 CG2 VAL A 542 53.707 43.543 58.662 1.00 55.81 C Atom 2120 C VAL A 542 50.969 45.962 59.867 1.00 59.15 C Atom 2121 O VAL A 542 51.198 46.233 61.045 1.00 59.44 O Atom 2122 N LEU A 543 49.778 46.118 59.300 1.00 58.76 N Atom 2123 CA LEU A 543 48.616 46.569 60.051 1.00 60.18 C Atom 2124 CB LEU A 543 47.793 47.547 59.214 1.00 58.00 C Atom 2125 CG LEU A 543 48.550 48.643 58.462 1.00 63.20 C Atom 2126 CD1 LEU A 543 47.574 49.527 57.697 1.00 58.91 C Atom 2127 CD2 LEU A 543 49.400 49.472 59.413 1.00 66.94 C Atom 2128 C LEU A 543 47.726 45.399 60.457 1.00 57.06 C Atom 2129 O LEU A 543 47.749 44.336 59.837 1.00 57.51 O Atom 2130 N GLU A 544 46.945 45.600 61.510 1.00 63.24 N Atom 2131 CA GLU A 544 45.856 44.691 61.820 1.00 60.38 C Atom 2132 CB GLU A 544 45.794 44.390 63.316 1.00 57.13 C Atom 2133 CG GLU A 544 44.755 43.344 63.684 1.00 65.52 C Atom 2134 CD GLU A 544 44.811 42.943 65.146 1.00 71.03 C Atom 2135 OE1 GLU A 544 45.922 42.675 65.650 1.00 67.70 O Atom 2136 OE2 GLU A 544 43.742 42.884 65.788 1.00 81.49 O Atom 2137 C GLU A 544 44.582 45.368 61.339 1.00 58.93 C Atom 2138 O GLU A 544 44.228 46.447 61.811 1.00 59.98 O Atom 2139 N ILE A 545 43.905 44.744 60.382 1.00 57.29 N Atom 2140 CA ILE A 545 42.787 45.389 59.706 1.00 59.18 C Atom 2141 CB ILE A 545 43.020 45.443 58.188 1.00 56.46 C Atom 2142 CG1 ILE A 545 43.180 44.027 57.631 1.00 52.09 C Atom 2143 CD1 ILE A 545 43.142 43.959 56.123 1.00 54.56 C Atom 2144 CG2 ILE A 545 44.236 46.298 57.871 1.00 58.41 C Atom 2145 C ILE A 545 41.437 44.721 59.963 1.00 58.70 C Atom 2146 O ILE A 545 40.422 45.122 59.391 1.00 58.95 O Atom 2147 N GLY A 546 41.420 43.704 60.816 1.00 55.55 N Atom 2148 CA GLY A 546 40.178 43.026 61.136 1.00 56.61 C Atom 2149 C GLY A 546 40.374 41.729 61.891 1.00 57.50 C Atom 2150 O GLY A 546 41.498 41.351 62.223 1.00 60.19 O Atom 2151 N ASP A 547 39.266 41.052 62.170 1.00 60.09 N Atom 2152 CA ASP A 547 39.298 39.753 62.827 1.00 61.20 C Atom 2153 CB ASP A 547 38.881 39.883 64.289 1.00 56.47 C Atom 2154 CG ASP A 547 40.059 40.158 65.200 1.00 64.54 C Atom 2155 OD1 ASP A 547 40.721 39.180 65.608 1.00 67.71 O Atom 2156 OD2 ASP A 547 40.323 41.340 65.512 1.00 57.58 O Atom 2157 C ASP A 547 38.412 38.765 62.086 1.00 57.02 C Atom 2158 O ASP A 547 37.321 39.114 61.644 1.00 58.76 O Atom 2159 N MET A 548 38.897 37.537 61.938 1.00 54.03 N Atom 2160 CA MET A 548 38.184 36.516 61.176 1.00 57.78 C Atom 2161 CB MET A 548 39.052 36.008 60.018 1.00 56.59 C Atom 2162 CG MET A 548 38.401 34.912 59.178 1.00 61.39 C Atom 2163 SD MET A 548 39.357 34.479 57.707 1.00 63.03 S Atom 2164 CE MET A 548 39.156 35.958 56.713 1.00 58.92 C Atom 2165 C MET A 548 37.718 35.343 62.040 1.00 61.19 C Atom 2166 O MET A 548 38.454 34.849 62.895 1.00 56.79 O Atom 2167 N LEU A 549 36.487 34.904 61.799 1.00 61.09 N Atom 2168 CA LEU A 549 35.908 33.761 62.496 1.00 62.00 C Atom 2169 CB LEU A 549 34.453 34.052 62.875 1.00 59.57 C Atom 2170 CG LEU A 549 34.202 34.705 64.238 1.00 52.87 C Atom 2171 CD1 LEU A 549 35.492 35.141 64.903 1.00 64.08 C Atom 2172 CD2 LEU A 549 33.248 35.872 64.103 1.00 54.21 C Atom 2173 C LEU A 549 36.000 32.511 61.626 1.00 62.40 C Atom 2174 O LEU A 549 35.408 32.449 60.551 1.00 66.69 O Atom 2175 N LEU A 550 36.744 31.515 62.094 1.00 62.44 N Atom 2176 CA LEU A 550 37.021 30.331 61.287 1.00 58.54 C Atom 2177 CB LEU A 550 38.531 30.134 61.139 1.00 67.54 C Atom 2178 CG LEU A 550 39.323 31.240 60.443 1.00 65.23 C Atom 2179 CD1 LEU A 550 40.813 31.046 60.670 1.00 68.77 C Atom 2180 CD2 LEU A 550 38.998 31.271 58.960 1.00 66.66 C Atom 2181 C LEU A 550 36.420 29.070 61.884 1.00 64.67 C Atom 2182 O LEU A 550 36.445 28.873 63.098 1.00 64.10 O Atom 2183 N ARG A 551 35.881 28.217 61.018 1.00 74.38 N Atom 2184 CA ARG A 551 35.447 26.883 61.415 1.00 74.55 C Atom 2185 CB ARG A 551 34.609 26.249 60.306 1.00 85.07 C Atom 2186 CG ARG A 551 33.260 26.919 60.082 1.00 92.20 C Atom 2187 CD ARG A 551 32.172 26.322 60.974 1.00 111.63 C Atom 2188 NE ARG A 551 32.378 26.612 62.393 1.00 110.91 N Atom 2189 CZ ARG A 551 31.674 26.068 63.381 1.00 106.62 C Atom 2190 NH1 ARG A 551 30.712 25.195 63.113 1.00 116.57 N Atom 2191 NH2 ARG A 551 31.935 26.394 64.640 1.00 96.37 N Atom 2192 C ARG A 551 36.677 26.030 61.703 1.00 75.39 C Atom 2193 O ARG A 551 37.673 26.106 60.984 1.00 74.27 O Atom 2194 N THR A 552 36.610 25.215 62.749 1.00 78.31 N Atom 2195 CA THR A 552 37.791 24.507 63.229 1.00 65.43 C Atom 2196 CB THR A 552 38.587 25.397 64.211 1.00 65.71 C Atom 2197 OG1 THR A 552 39.433 26.287 63.471 1.00 73.96 O Atom 2198 CG2 THR A 552 39.441 24.562 65.148 1.00 71.93 C Atom 2199 C THR A 552 37.435 23.181 63.891 1.00 68.81 C Atom 2200 O THR A 552 36.303 22.983 64.337 1.00 72.99 O Atom 2201 N ALA A 553 38.402 22.270 63.936 1.00 70.81 N Atom 2202 CA ALA A 553 38.220 20.982 64.591 1.00 69.85 C Atom 2203 CB ALA A 553 39.550 20.245 64.678 1.00 73.57 C Atom 2204 C ALA A 553 37.600 21.129 65.975 1.00 72.49 C Atom 2205 O ALA A 553 36.897 20.235 66.445 1.00 76.32 O Atom 2206 N ILE A 554 37.863 22.257 66.627 1.00 66.54 N Atom 2207 CA ILE A 554 37.331 22.500 67.967 1.00 69.18 C Atom 2208 CB ILE A 554 38.426 22.962 68.944 1.00 71.86 C Atom 2209 CG1 ILE A 554 38.879 24.384 68.600 1.00 74.24 C Atom 2210 CD1 ILE A 554 39.735 25.028 69.669 1.00 67.63 C Atom 2211 CG2 ILE A 554 39.594 21.985 68.927 1.00 67.10 C Atom 2212 C ILE A 554 36.194 23.524 67.984 1.00 65.55 C Atom 2213 O ILE A 554 35.652 23.838 69.043 1.00 65.49 O Atom 2214 N GLY A 555 35.834 24.039 66.813 1.00 66.23 N Atom 2215 CA GLY A 555 34.749 25.000 66.707 1.00 67.71 C Atom 2216 C GLY A 555 35.170 26.329 66.102 1.00 67.68 C Atom 2217 O GLY A 555 36.166 26.410 65.387 1.00 68.02 O Atom 2218 N GLN A 556 34.409 27.379 66.389 1.00 66.99 N Atom 2219 CA GLN A 556 34.718 28.703 65.856 1.00 67.72 C Atom 2220 CB GLN A 556 33.479 29.604 65.865 1.00 59.52 C Atom 2221 CG GLN A 556 33.669 30.910 65.109 1.00 68.01 C Atom 2222 CD GLN A 556 32.375 31.698 64.938 1.00 76.12 C Atom 2223 OE1 GLN A 556 31.768 32.146 65.914 1.00 68.44 O Atom 2224 NE2 GLN A 556 31.959 31.886 63.689 1.00 64.44 N Atom 2225 C GLN A 556 35.873 29.357 66.614 1.00 65.53 C Atom 2226 O GLN A 556 35.861 29.442 67.843 1.00 61.10 O Atom 2227 N VAL A 557 36.876 29.809 65.870 1.00 59.82 N Atom 2228 CA VAL A 557 38.034 30.458 66.469 1.00 60.39 C Atom 2229 CB VAL A 557 39.302 29.601 66.301 1.00 60.85 C Atom 2230 CG1 VAL A 557 39.715 29.536 64.843 1.00 68.63 C Atom 2231 CG2 VAL A 557 40.427 30.148 67.158 1.00 61.54 C Atom 2232 C VAL A 557 38.250 31.839 65.845 1.00 61.67 C Atom 2233 O VAL A 557 38.012 32.033 64.653 1.00 63.73 O Atom 2234 N SER A 558 38.681 32.800 66.656 1.00 57.17 N Atom 2235 CA SER A 558 38.893 34.162 66.180 1.00 58.11 C Atom 2236 CB SER A 558 38.361 35.171 67.205 1.00 63.20 C Atom 2237 OG SER A 558 38.298 36.485 66.662 1.00 60.40 O Atom 2238 C SER A 558 40.373 34.415 65.904 1.00 61.95 C Atom 2239 O SER A 558 41.208 34.294 66.799 1.00 64.06 O Atom 2240 N ARG A 559 40.691 34.758 64.659 1.00 57.79 N Atom 2241 CA ARG A 559 42.067 35.051 64.267 1.00 57.32 C Atom 2242 CB ARG A 559 42.590 34.016 63.267 1.00 61.25 C Atom 2243 CG ARG A 559 42.869 32.651 63.859 1.00 66.58 C Atom 2244 CD ARG A 559 43.692 31.793 62.910 1.00 76.71 C Atom 2245 NE ARG A 559 44.955 32.436 62.554 1.00 80.53 N Atom 2246 CZ ARG A 559 45.967 31.826 61.944 1.00 79.06 C Atom 2247 NH1 ARG A 559 45.878 30.543 61.618 1.00 75.87 N Atom 2248 NH2 ARG A 559 47.073 32.500 61.663 1.00 71.23 N Atom 2249 C ARG A 559 42.175 36.433 63.652 1.00 60.18 C Atom 2250 O ARG A 559 41.375 36.793 62.791 1.00 61.02 O Atom 2251 N PRO A 560 43.175 37.210 64.089 1.00 57.81 N Atom 2252 CA PRO A 560 43.402 38.540 63.523 1.00 56.89 C Atom 2253 CB PRO A 560 44.659 39.016 64.253 1.00 55.57 C Atom 2254 CG PRO A 560 44.678 38.234 65.523 1.00 53.08 C Atom 2255 CD PRO A 560 44.120 36.898 65.174 1.00 54.59 C Atom 2256 C PRO A 560 43.681 38.452 62.030 1.00 55.23 C Atom 2257 O PRO A 560 44.338 37.514 61.584 1.00 52.89 O Atom 2258 N MET A 561 43.168 39.409 61.267 1.00 56.89 N Atom 2259 CA MET A 561 43.555 39.544 59.871 1.00 53.86 C Atom 2260 CB MET A 561 42.340 39.725 58.958 1.00 50.96 C Atom 2261 CG MET A 561 42.734 40.088 57.532 1.00 52.87 C Atom 2262 SD MET A 561 41.553 39.589 56.269 1.00 65.15 S Atom 2263 CE MET A 561 40.467 41.012 56.246 1.00 60.75 C Atom 2264 C MET A 561 44.513 40.719 59.713 1.00 57.06 C Atom 2265 O MET A 561 44.234 41.832 60.167 1.00 52.26 O Atom 2266 N PHE A 562 45.644 40.464 59.067 1.00 59.13 N Atom 2267 CA PHE A 562 46.660 41.491 58.897 1.00 57.32 C Atom 2268 CB PHE A 562 48.029 40.967 59.334 1.00 54.50 C Atom 2269 CG PHE A 562 48.043 40.403 60.720 1.00 53.66 C Atom 2270 CD1 PHE A 562 48.125 41.241 61.818 1.00 51.40 C Atom 2271 CE1 PHE A 562 48.134 40.728 63.098 1.00 53.69 C Atom 2272 CZ PHE A 562 48.060 39.360 63.291 1.00 55.77 C Atom 2273 CE2 PHE A 562 47.976 38.516 62.204 1.00 55.07 C Atom 2274 CD2 PHE A 562 47.966 39.036 60.928 1.00 53.44 C Atom 2275 C PHE A 562 46.726 41.968 57.460 1.00 54.19 C Atom 2276 O PHE A 562 46.364 41.246 56.531 1.00 53.63 O Atom 2277 N LEU A 563 47.180 43.203 57.294 1.00 53.04 N Atom 2278 CA LEU A 563 47.472 43.750 55.982 1.00 53.62 C Atom 2279 CB LEU A 563 46.682 45.035 55.741 1.00 51.30 C Atom 2280 CG LEU A 563 46.744 45.572 54.308 1.00 56.06 C Atom 2281 CD1 LEU A 563 45.949 44.681 53.358 1.00 56.80 C Atom 2282 CD2 LEU A 563 46.252 47.006 54.244 1.00 56.09 C Atom 2283 C LEU A 563 48.963 44.045 55.898 1.00 55.06 C Atom 2284 O LEU A 563 49.467 44.937 56.579 1.00 58.37 O Atom 2285 N TYR A 564 49.670 43.284 55.072 1.00 53.83 N Atom 2286 CA TYR A 564 51.088 43.526 54.854 1.00 53.77 C Atom 2287 CB TYR A 564 51.792 42.242 54.424 1.00 50.50 C Atom 2288 CG TYR A 564 52.042 41.287 55.569 1.00 53.43 C Atom 2289 CD1 TYR A 564 51.013 40.517 56.096 1.00 52.87 C Atom 2290 CE1 TYR A 564 51.242 39.646 57.146 1.00 53.89 C Atom 2291 CZ TYR A 564 52.508 39.540 57.681 1.00 54.15 C Atom 2292 OH TYR A 564 52.738 38.673 58.723 1.00 54.94 O Atom 2293 CE2 TYR A 564 53.542 40.298 57.178 1.00 51.54 C Atom 2294 CD2 TYR A 564 53.306 41.164 56.131 1.00 50.49 C Atom 2295 C TYR A 564 51.292 44.628 53.825 1.00 54.76 C Atom 2296 O TYR A 564 50.831 44.526 52.693 1.00 56.37 O Atom 2297 N VAL A 565 51.977 45.689 54.232 1.00 53.43 N Atom 2298 CA VAL A 565 52.178 46.844 53.367 1.00 55.63 C Atom 2299 CB VAL A 565 51.541 48.109 53.970 1.00 57.71 C Atom 2300 CG1 VAL A 565 51.442 49.198 52.922 1.00 57.66 C Atom 2301 CG2 VAL A 565 50.166 47.792 54.547 1.00 56.42 C Atom 2302 C VAL A 565 53.659 47.113 53.135 1.00 60.14 C Atom 2303 O VAL A 565 54.476 46.966 54.041 1.00 65.88 O Atom 2304 N ARG A 566 54.004 47.509 51.916 1.00 60.62 N Atom 2305 CA ARG A 566 55.377 47.877 51.601 1.00 60.55 C Atom 2306 CB ARG A 566 56.268 46.637 51.524 1.00 58.95 C Atom 2307 CG ARG A 566 55.956 45.724 50.348 1.00 55.73 C Atom 2308 CD ARG A 566 57.163 44.887 49.964 1.00 54.02 C Atom 2309 NE ARG A 566 58.109 45.662 49.170 1.00 69.19 N Atom 2310 CZ ARG A 566 59.348 45.267 48.891 1.00 62.92 C Atom 2311 NH1 ARG A 566 59.801 44.103 49.345 1.00 68.11 N Atom 2312 NH2 ARG A 566 60.142 46.034 48.158 1.00 59.65 N Atom 2313 C ARG A 566 55.445 48.638 50.287 1.00 64.51 C Atom 2314 O ARG A 566 54.603 48.453 49.408 1.00 63.97 O Atom 2315 N THR A 567 56.452 49.496 50.160 1.00 70.40 N Atom 2316 CA THR A 567 56.695 50.196 48.906 1.00 69.23 C Atom 2317 CB THR A 567 57.416 51.542 49.125 1.00 69.59 C Atom 2318 OG1 THR A 567 58.707 51.305 49.698 1.00 73.75 O Atom 2319 CG2 THR A 567 56.608 52.440 50.053 1.00 64.50 C Atom 2320 C THR A 567 57.541 49.296 48.017 1.00 68.45 C Atom 2321 O THR A 567 58.208 48.384 48.505 1.00 58.68 O Atom 2322 N ASN A 568 57.507 49.549 46.713 1.00 72.84 N Atom 2323 CA ASN A 568 58.198 48.695 45.758 1.00 68.68 C Atom 2324 CB ASN A 568 57.522 47.327 45.709 1.00 64.61 C Atom 2325 CG ASN A 568 58.500 46.204 45.473 1.00 66.48 C Atom 2326 OD1 ASN A 568 58.270 45.071 45.895 1.00 72.14 O Atom 2327 ND2 ASN A 568 59.604 46.509 44.805 1.00 67.22 N Atom 2328 C ASN A 568 58.202 49.330 44.374 1.00 68.09 C Atom 2329 O ASN A 568 57.796 50.480 44.214 1.00 69.75 O Atom 2330 N GLY A 569 58.657 48.581 43.374 1.00 67.65 N Atom 2331 CA GLY A 569 58.696 49.083 42.014 1.00 72.00 C Atom 2332 C GLY A 569 59.086 48.031 40.995 1.00 70.54 C Atom 2333 O GLY A 569 59.764 47.059 41.318 1.00 71.47 O Atom 2334 N THR A 570 58.643 48.226 39.758 1.00 74.61 N Atom 2335 CA THR A 570 59.023 47.353 38.654 1.00 81.59 C Atom 2336 CB THR A 570 57.959 46.272 38.372 1.00 79.46 C Atom 2337 OG1 THR A 570 56.659 46.783 38.689 1.00 80.41 O Atom 2338 CG2 THR A 570 58.226 45.027 39.202 1.00 91.22 C Atom 2339 C THR A 570 59.240 48.161 37.385 1.00 85.13 C Atom 2340 O THR A 570 59.124 49.384 37.389 1.00 82.78 O Atom 2341 N SER A 571 59.561 47.462 36.304 1.00 90.28 N Atom 2342 CA SER A 571 59.759 48.082 35.004 1.00 88.63 C Atom 2343 CB SER A 571 61.243 48.083 34.632 1.00 94.51 C Atom 2344 OG SER A 571 61.750 46.761 34.557 1.00 85.31 O Atom 2345 C SER A 571 58.967 47.302 33.968 1.00 94.66 C Atom 2346 O SER A 571 58.517 46.186 34.235 1.00 93.43 O Atom 2347 N LYS A 572 58.797 47.891 32.790 1.00 103.65 N Atom 2348 CA LYS A 572 58.123 47.216 31.692 1.00 96.24 C Atom 2349 CB LYS A 572 58.278 48.024 30.406 1.00 103.60 C Atom 2350 CG LYS A 572 57.890 49.486 30.546 1.00 110.08 C Atom 2351 CD LYS A 572 56.434 49.713 30.177 1.00 114.59 C Atom 2352 CE LYS A 572 56.280 49.927 28.678 1.00 122.51 C Atom 2353 NZ LYS A 572 56.973 51.167 28.217 1.00 129.13 N Atom 2354 C LYS A 572 58.725 45.831 31.508 1.00 89.59 C Atom 2355 O LYS A 572 58.012 44.861 31.256 1.00 89.83 O Atom 2356 N ILE A 573 60.046 45.749 31.642 1.00 90.26 N Atom 2357 CA ILE A 573 60.764 44.489 31.467 1.00 94.27 C Atom 2358 CB ILE A 573 62.294 44.705 31.366 1.00 92.18 C Atom 2359 CG1 ILE A 573 62.696 44.875 29.902 1.00 90.68 C Atom 2360 CD1 ILE A 573 62.358 43.671 29.040 1.00 99.11 C Atom 2361 CG2 ILE A 573 63.054 43.528 31.969 1.00 90.52 C Atom 2362 C ILE A 573 60.447 43.471 32.558 1.00 89.39 C Atom 2363 O ILE A 573 60.192 42.301 32.265 1.00 86.24 O Atom 2364 N LYS A 574 60.464 43.914 33.811 1.00 87.88 N Atom 2365 CA LYS A 574 60.170 43.022 34.927 1.00 90.51 C Atom 2366 CB LYS A 574 60.469 43.701 36.266 1.00 89.12 C Atom 2367 CG LYS A 574 61.948 43.967 36.507 1.00 86.87 C Atom 2368 CD LYS A 574 62.225 44.339 37.957 1.00 91.09 C Atom 2369 CE LYS A 574 62.070 43.140 38.884 1.00 110.36 C Atom 2370 NZ LYS A 574 62.506 43.451 40.277 1.00 105.47 N Atom 2371 C LYS A 574 58.719 42.554 34.871 1.00 88.76 C Atom 2372 O LYS A 574 58.417 41.396 35.167 1.00 87.21 O Atom 2373 N MET A 575 57.826 43.459 34.483 1.00 81.99 N Atom 2374 CA MET A 575 56.423 43.112 34.299 1.00 82.20 C Atom 2375 CB MET A 575 55.582 44.363 34.037 1.00 78.68 C Atom 2376 CG MET A 575 55.222 45.135 35.295 1.00 79.94 C Atom 2377 SD MET A 575 54.296 46.642 34.949 1.00 91.59 S Atom 2378 CE MET A 575 55.607 47.735 34.405 1.00 92.30 C Atom 2379 C MET A 575 56.247 42.113 33.163 1.00 82.95 C Atom 2380 O MET A 575 55.407 41.220 33.235 1.00 84.88 O Atom 2381 N LYS A 576 57.044 42.273 32.113 1.00 83.05 N Atom 2382 CA LYS A 576 56.997 41.366 30.972 1.00 89.65 C Atom 2383 CB LYS A 576 57.909 41.871 29.850 1.00 94.69 C Atom 2384 CG LYS A 576 57.998 40.946 28.642 1.00 97.97 C Atom 2385 CD LYS A 576 56.953 41.276 27.576 1.00 109.02 C Atom 2386 CE LYS A 576 55.558 40.790 27.956 1.00 110.12 C Atom 2387 NZ LYS A 576 54.572 41.029 26.860 1.00 109.27 N Atom 2388 C LYS A 576 57.406 39.955 31.384 1.00 86.53 C Atom 2389 O LYS A 576 56.720 38.981 31.071 1.00 78.88 O Atom 2390 N TRP A 577 58.529 39.851 32.086 1.00 85.93 N Atom 2391 CA TRP A 577 59.009 38.558 32.552 1.00 90.21 C Atom 2392 CB TRP A 577 60.342 38.706 33.289 1.00 91.13 C Atom 2393 CG TRP A 577 61.491 39.154 32.425 1.00 106.51 C Atom 2394 CD1 TRP A 577 62.481 40.029 32.772 1.00 110.83 C Atom 2395 NE1 TRP A 577 63.360 40.188 31.729 1.00 114.42 N Atom 2396 CE2 TRP A 577 62.949 39.414 30.678 1.00 122.04 C Atom 2397 CD2 TRP A 577 61.773 38.746 31.077 1.00 116.88 C Atom 2398 CE3 TRP A 577 61.147 37.881 30.172 1.00 120.02 C Atom 2399 CZ3 TRP A 577 61.706 37.717 28.916 1.00 126.40 C Atom 2400 CH2 TRP A 577 62.877 38.396 28.548 1.00 127.91 C Atom 2401 CZ2 TRP A 577 63.511 39.246 29.412 1.00 129.15 C Atom 2402 C TRP A 577 57.977 37.897 33.462 1.00 87.70 C Atom 2403 O TRP A 577 57.800 36.676 33.439 1.00 82.92 O Atom 2404 N GLY A 578 57.297 38.716 34.258 1.00 86.34 N Atom 2405 CA GLY A 578 56.281 38.232 35.175 1.00 80.98 C Atom 2406 C GLY A 578 55.047 37.739 34.450 1.00 80.29 C Atom 2407 O GLY A 578 54.420 36.765 34.864 1.00 76.48 O Atom 2408 N MET A 579 54.698 38.416 33.361 1.00 78.84 N Atom 2409 CA MET A 579 53.549 38.030 32.552 1.00 79.56 C Atom 2410 CB MET A 579 53.208 39.132 31.547 1.00 78.76 C Atom 2411 CG MET A 579 52.655 40.402 32.168 1.00 83.74 C Atom 2412 SD MET A 579 52.295 41.660 30.927 1.00 82.84 S Atom 2413 CE MET A 579 51.105 40.791 29.906 1.00 80.08 C Atom 2414 C MET A 579 53.800 36.718 31.812 1.00 80.84 C Atom 2415 O MET A 579 52.891 36.158 31.197 1.00 81.46 O Atom 2416 N GLU A 580 55.034 36.230 31.878 1.00 79.43 N Atom 2417 CA GLU A 580 55.422 35.038 31.136 1.00 81.85 C Atom 2418 CB GLU A 580 56.549 35.372 30.159 1.00 87.44 C Atom 2419 CG GLU A 580 56.161 36.356 29.070 1.00 91.90 C Atom 2420 CD GLU A 580 57.357 36.829 28.268 1.00 108.07 C Atom 2421 OE1 GLU A 580 58.497 36.659 28.753 1.00 105.20 O Atom 2422 OE2 GLU A 580 57.157 37.369 27.158 1.00 113.44 O Atom 2423 C GLU A 580 55.850 33.899 32.052 1.00 83.65 C Atom 2424 O GLU A 580 56.486 32.946 31.610 1.00 82.11 O Atom 2425 N MET A 581 55.489 33.989 33.327 1.00 84.29 N Atom 2426 CA MET A 581 55.878 32.961 34.288 1.00 76.89 C Atom 2427 CB MET A 581 55.399 33.318 35.694 1.00 75.91 C Atom 2428 CG MET A 581 56.130 34.495 36.310 1.00 76.20 C Atom 2429 SD MET A 581 55.676 34.747 38.033 1.00 77.39 S Atom 2430 CE MET A 581 56.086 33.147 38.725 1.00 64.00 C Atom 2431 C MET A 581 55.383 31.571 33.895 1.00 76.68 C Atom 2432 O MET A 581 55.820 30.568 34.461 1.00 74.32 O Atom 2433 N ARG A 582 54.473 31.516 32.927 1.00 80.33 N Atom 2434 CA ARG A 582 54.011 30.243 32.385 1.00 78.04 C Atom 2435 CB ARG A 582 53.011 30.467 31.250 1.00 87.55 C Atom 2436 CG ARG A 582 51.629 30.911 31.697 1.00 92.16 C Atom 2437 CD ARG A 582 50.661 30.902 30.525 1.00 95.36 C Atom 2438 NE ARG A 582 49.304 31.286 30.907 1.00 94.28 N Atom 2439 CZ ARG A 582 48.815 32.517 30.795 1.00 97.90 C Atom 2440 NH1 ARG A 582 49.575 33.493 30.315 1.00 83.31 N Atom 2441 NH2 ARG A 582 47.567 32.771 31.164 1.00 110.81 N Atom 2442 C ARG A 582 55.190 29.425 31.871 1.00 80.28 C Atom 2443 O ARG A 582 55.143 28.194 31.849 1.00 79.98 O Atom 2444 N ARG A 583 56.243 30.120 31.452 1.00 79.90 N Atom 2445 CA ARG A 583 57.446 29.467 30.954 1.00 77.94 C Atom 2446 CB ARG A 583 58.555 30.491 30.710 1.00 83.44 C Atom 2447 CG ARG A 583 58.185 31.626 29.771 1.00 91.82 C Atom 2448 CD ARG A 583 58.270 31.212 28.314 1.00 101.01 C Atom 2449 NE ARG A 583 58.299 32.378 27.434 1.00 113.97 N Atom 2450 CZ ARG A 583 59.399 33.066 27.142 1.00 121.99 C Atom 2451 NH1 ARG A 583 60.565 32.703 27.658 1.00 118.47 N Atom 2452 NH2 ARG A 583 59.332 34.116 26.334 1.00 115.39 N Atom 2453 C ARG A 583 57.930 28.426 31.952 1.00 77.46 C Atom 2454 O ARG A 583 58.478 27.394 31.570 1.00 83.61 O Atom 2455 N CYS A 584 57.724 28.705 33.235 1.00 73.39 N Atom 2456 CA CYS A 584 58.135 27.792 34.297 1.00 73.01 C Atom 2457 CB CYS A 584 57.755 28.354 35.667 1.00 68.49 C Atom 2458 SG CYS A 584 58.475 29.973 36.023 1.00 70.75 S Atom 2459 C CYS A 584 57.525 26.407 34.105 1.00 75.13 C Atom 2460 O CYS A 584 58.168 25.394 34.375 1.00 73.34 O Atom 2461 N LEU A 585 56.281 26.373 33.637 1.00 79.70 N Atom 2462 CA LEU A 585 55.607 25.116 33.342 1.00 78.19 C Atom 2463 CB LEU A 585 54.169 25.378 32.896 1.00 72.50 C Atom 2464 CG LEU A 585 53.207 25.894 33.969 1.00 73.82 C Atom 2465 CD1 LEU A 585 51.983 26.530 33.330 1.00 68.84 C Atom 2466 CD2 LEU A 585 52.802 24.779 34.929 1.00 67.02 C Atom 2467 C LEU A 585 56.364 24.354 32.261 1.00 80.59 C Atom 2468 O LEU A 585 56.652 23.166 32.408 1.00 77.85 O Atom 2469 N LEU A 586 56.687 25.050 31.176 1.00 80.81 N Atom 2470 CA LEU A 586 57.440 24.461 30.076 1.00 81.21 C Atom 2471 CB LEU A 586 57.602 25.473 28.941 1.00 87.19 C Atom 2472 CG LEU A 586 56.468 25.513 27.914 1.00 98.03 C Atom 2473 CD1 LEU A 586 56.254 26.924 27.384 1.00 84.88 C Atom 2474 CD2 LEU A 586 56.743 24.533 26.780 1.00 92.36 C Atom 2475 C LEU A 586 58.802 23.964 30.539 1.00 85.77 C Atom 2476 O LEU A 586 59.089 22.770 30.473 1.00 88.44 O Atom 2477 N GLN A 587 59.638 24.885 31.009 1.00 84.94 N Atom 2478 CA GLN A 587 60.967 24.536 31.494 1.00 85.74 C Atom 2479 CB GLN A 587 61.630 25.739 32.167 1.00 85.36 C Atom 2480 CG GLN A 587 62.995 25.430 32.763 1.00 93.76 C Atom 2481 CD GLN A 587 63.654 26.644 33.390 1.00 100.97 C Atom 2482 OE1 GLN A 587 62.999 27.453 34.050 1.00 104.32 O Atom 2483 NE2 GLN A 587 64.960 26.776 33.187 1.00 107.44 N Atom 2484 C GLN A 587 60.905 23.364 32.467 1.00 85.97 C Atom 2485 O GLN A 587 61.665 22.402 32.349 1.00 90.29 O Atom 2486 N SER A 588 59.994 23.452 33.428 1.00 84.24 N Atom 2487 CA SER A 588 59.819 22.394 34.415 1.00 81.50 C Atom 2488 CB SER A 588 58.726 22.775 35.414 1.00 77.11 C Atom 2489 OG SER A 588 58.613 21.811 36.441 1.00 87.51 O Atom 2490 C SER A 588 59.474 21.075 33.730 1.00 89.39 C Atom 2491 O SER A 588 60.046 20.030 34.044 1.00 88.83 O Atom 2492 N LEU A 589 58.539 21.138 32.787 1.00 88.86 N Atom 2493 CA LEU A 589 58.118 19.965 32.030 1.00 90.66 C Atom 2494 CB LEU A 589 57.025 20.346 31.028 1.00 90.84 C Atom 2495 CG LEU A 589 56.750 19.354 29.894 1.00 89.79 C Atom 2496 CD1 LEU A 589 56.311 18.007 30.444 1.00 88.21 C Atom 2497 CD2 LEU A 589 55.708 19.910 28.933 1.00 80.65 C Atom 2498 C LEU A 589 59.286 19.311 31.298 1.00 88.50 C Atom 2499 O LEU A 589 59.521 18.112 31.439 1.00 91.08 O Atom 2500 N GLN A 590 60.010 20.105 30.515 1.00 86.90 N Atom 2501 CA GLN A 590 61.128 19.598 29.725 1.00 94.65 C Atom 2502 CB GLN A 590 61.840 20.748 29.011 1.00 89.39 C Atom 2503 CG GLN A 590 61.010 21.386 27.910 1.00 95.11 C Atom 2504 CD GLN A 590 61.704 22.565 27.262 1.00 104.97 C Atom 2505 OE1 GLN A 590 62.819 22.928 27.638 1.00 110.06 O Atom 2506 NE2 GLN A 590 61.045 23.174 26.282 1.00 105.62 N Atom 2507 C GLN A 590 62.117 18.786 30.562 1.00 95.48 C Atom 2508 O GLN A 590 62.571 17.723 30.139 1.00 97.49 O Atom 2509 N GLN A 591 62.444 19.289 31.748 1.00 91.96 N Atom 2510 CA GLN A 591 63.331 18.570 32.655 1.00 89.24 C Atom 2511 CB GLN A 591 63.584 19.384 33.926 1.00 88.53 C Atom 2512 CG GLN A 591 64.574 20.523 33.745 1.00 91.99 C Atom 2513 CD GLN A 591 64.444 21.591 34.817 1.00 92.85 C Atom 2514 OE1 GLN A 591 64.951 22.703 34.666 1.00 101.97 O Atom 2515 NE2 GLN A 591 63.754 21.260 35.903 1.00 88.24 N Atom 2516 C GLN A 591 62.751 17.206 33.003 1.00 96.77 C Atom 2517 O GLN A 591 63.447 16.193 32.948 1.00 99.31 O Atom 2518 N ILE A 592 61.470 17.184 33.353 1.00 96.10 N Atom 2519 CA ILE A 592 60.799 15.937 33.687 1.00 98.52 C Atom 2520 CB ILE A 592 59.357 16.187 34.170 1.00 92.47 C Atom 2521 CG1 ILE A 592 59.126 15.534 35.531 1.00 87.96 C Atom 2522 CD1 ILE A 592 59.842 16.233 36.652 1.00 84.37 C Atom 2523 CG2 ILE A 592 58.348 15.700 33.143 1.00 91.65 C Atom 2524 C ILE A 592 60.768 15.041 32.453 1.00 105.06 C Atom 2525 O ILE A 592 60.803 13.814 32.555 1.00 108.33 O Atom 2526 N GLU A 593 60.713 15.673 31.285 1.00 103.14 N Atom 2527 CA GLU A 593 60.631 14.959 30.019 1.00 104.18 C Atom 2528 CB GLU A 593 60.296 15.933 28.888 1.00 101.17 C Atom 2529 CG GLU A 593 59.492 15.325 27.755 1.00 108.35 C Atom 2530 CD GLU A 593 58.666 16.359 27.009 1.00 118.82 C Atom 2531 OE1 GLU A 593 57.527 16.034 26.607 1.00 122.29 O Atom 2532 OE2 GLU A 593 59.149 17.499 26.834 1.00 107.72 O Atom 2533 C GLU A 593 61.941 14.234 29.731 1.00 108.72 C Atom 2534 O GLU A 593 61.971 13.009 29.618 1.00 116.41 O Atom 2535 N SER A 594 63.025 14.996 29.628 1.00 101.91 N Atom 2536 CA SER A 594 64.339 14.420 29.377 1.00 106.59 C Atom 2537 CB SER A 594 65.404 15.516 29.318 1.00 110.69 C Atom 2538 OG SER A 594 65.785 15.928 30.619 1.00 106.08 O Atom 2539 C SER A 594 64.700 13.411 30.461 1.00 110.87 C Atom 2540 O SER A 594 65.326 12.387 30.188 1.00 112.95 O Atom 2541 N MET A 595 64.297 13.710 31.691 1.00 109.65 N Atom 2542 CA MET A 595 64.594 12.849 32.828 1.00 108.13 C Atom 2543 CB MET A 595 63.981 13.427 34.104 1.00 105.82 C Atom 2544 CG MET A 595 64.812 13.197 35.354 1.00 98.80 C Atom 2545 SD MET A 595 64.051 13.912 36.824 1.00 95.38 S Atom 2546 CE MET A 595 62.951 12.588 37.314 1.00 98.54 C Atom 2547 C MET A 595 64.059 11.444 32.578 1.00 108.36 C Atom 2548 O MET A 595 64.528 10.472 33.170 1.00 108.23 O Atom 2549 N ILE A 596 63.070 11.349 31.695 1.00 113.18 N Atom 2550 CA ILE A 596 62.483 10.067 31.326 1.00 117.43 C Atom 2551 CB ILE A 596 61.047 10.232 30.791 1.00 122.06 C Atom 2552 CG1 ILE A 596 60.079 10.490 31.949 1.00 121.40 C Atom 2553 CD1 ILE A 596 58.663 10.789 31.513 1.00 116.32 C Atom 2554 CG2 ILE A 596 60.619 8.998 30.015 1.00 125.91 C Atom 2555 C ILE A 596 63.348 9.344 30.297 1.00 124.38 C Atom 2556 O ILE A 596 63.467 8.121 30.328 1.00 129.89 O Atom 2557 N GLU A 597 63.954 10.107 29.390 1.00 125.14 N Atom 2558 CA GLU A 597 64.857 9.537 28.395 1.00 123.86 C Atom 2559 CB GLU A 597 65.345 10.613 27.421 1.00 117.57 C Atom 2560 CG GLU A 597 64.232 11.461 26.840 1.00 117.68 C Atom 2561 CD GLU A 597 63.012 10.637 26.498 1.00 121.96 C Atom 2562 OE1 GLU A 597 61.939 10.906 27.076 1.00 123.05 O Atom 2563 OE2 GLU A 597 63.131 9.710 25.670 1.00 123.26 O Atom 2564 C GLU A 597 66.044 8.876 29.083 1.00 125.65 C Atom 2565 O GLU A 597 66.532 7.836 28.642 1.00 130.69 O Atom 2566 N ALA A 598 66.498 9.486 30.174 1.00 125.03 N Atom 2567 CA ALA A 598 67.601 8.939 30.956 1.00 129.41 C Atom 2568 CB ALA A 598 68.103 9.967 31.960 1.00 124.65 C Atom 2569 C ALA A 598 67.174 7.660 31.667 1.00 127.26 C Atom 2570 O ALA A 598 67.869 7.168 32.556 1.00 135.33 O Atom 2571 N GLU A 599 66.021 7.130 31.269 1.00 121.61 N Atom 2572 CA GLU A 599 65.491 5.898 31.840 1.00 126.72 C Atom 2573 CB GLU A 599 64.496 6.212 32.961 1.00 123.72 C Atom 2574 CG GLU A 599 65.119 6.792 34.223 1.00 124.71 C Atom 2575 CD GLU A 599 65.700 5.729 35.138 1.00 118.48 C Atom 2576 OE1 GLU A 599 65.984 6.051 36.312 1.00 112.27 O Atom 2577 OE2 GLU A 599 65.866 4.575 34.689 1.00 117.88 O Atom 2578 C GLU A 599 64.817 5.045 30.767 1.00 131.61 C Atom 2579 O GLU A 599 64.898 3.818 30.797 1.00 136.49 O Atom 2580 N SER A 600 64.151 5.704 29.823 1.00 129.93 N Atom 2581 CA SER A 600 63.448 5.013 28.744 1.00 130.99 C Atom 2582 CB SER A 600 62.472 5.959 28.039 1.00 129.03 C Atom 2583 OG SER A 600 61.269 6.093 28.774 1.00 128.30 O Atom 2584 C SER A 600 64.408 4.409 27.727 1.00 137.49 C Atom 2585 O SER A 600 64.177 3.311 27.219 1.00 138.88 O Atom 2586 N SER A 601 65.480 5.132 27.424 1.00 136.51 N Atom 2587 CA SER A 601 66.476 4.643 26.481 1.00 133.98 C Atom 2588 CB SER A 601 67.457 5.756 26.112 1.00 127.75 C Atom 2589 OG SER A 601 68.122 5.465 24.895 1.00 134.97 O Atom 2590 C SER A 601 67.219 3.448 27.072 1.00 135.39 C Atom 2591 O SER A 601 67.679 2.568 26.345 1.00 132.66 O Atom 2592 N VAL A 602 67.324 3.423 28.398 1.00 134.47 N Atom 2593 CA VAL A 602 67.991 2.333 29.104 1.00 139.35 C Atom 2594 CB VAL A 602 68.510 2.789 30.486 1.00 139.31 C Atom 2595 CG1 VAL A 602 68.512 1.630 31.477 1.00 130.99 C Atom 2596 CG2 VAL A 602 69.898 3.391 30.353 1.00 133.83 C Atom 2597 C VAL A 602 67.087 1.114 29.275 1.00 137.84 C Atom 2598 O VAL A 602 67.519 −0.021 29.072 1.00 137.87 O Atom 2599 N LYS A 603 65.834 1.354 29.646 1.00 139.99 N Atom 2600 CA LYS A 603 64.883 0.270 29.873 1.00 141.53 C Atom 2601 CB LYS A 603 63.797 0.702 30.862 1.00 140.37 C Atom 2602 CG LYS A 603 64.265 0.761 32.310 1.00 139.98 C Atom 2603 CD LYS A 603 64.751 −0.603 32.783 1.00 142.83 C Atom 2604 CE LYS A 603 65.271 −0.545 34.212 1.00 137.68 C Atom 2605 NZ LYS A 603 65.851 −1.847 34.650 1.00 126.51 N Atom 2606 C LYS A 603 64.252 −0.225 28.572 1.00 139.44 C Atom 2607 O LYS A 603 63.428 −1.141 28.584 1.00 132.71 O Atom 2608 N GLU A 604 64.644 0.390 27.460 1.00 139.80 N Atom 2609 CA GLU A 604 64.184 −0.011 26.130 1.00 138.14 C Atom 2610 CB GLU A 604 64.392 −1.514 25.908 1.00 140.13 C Atom 2611 CG GLU A 604 65.857 −1.928 25.871 1.00 135.79 C Atom 2612 CD GLU A 604 66.047 −3.426 25.721 1.00 131.91 C Atom 2613 OE1 GLU A 604 67.090 −3.939 26.179 1.00 118.77 O Atom 2614 OE2 GLU A 604 65.155 −4.090 25.149 1.00 130.37 O Atom 2615 C GLU A 604 62.736 0.388 25.841 1.00 138.57 C Atom 2616 O GLU A 604 62.427 0.879 24.755 1.00 136.63 O Atom 2617 N LYS A 605 61.854 0.179 26.813 1.00 141.21 N Atom 2618 CA LYS A 605 60.452 0.562 26.668 1.00 138.83 C Atom 2619 CB LYS A 605 59.545 −0.424 27.413 1.00 132.36 C Atom 2620 CG LYS A 605 58.110 0.056 27.581 1.00 134.62 C Atom 2621 CD LYS A 605 57.303 −0.869 28.477 1.00 139.57 C Atom 2622 CE LYS A 605 56.035 −0.184 28.974 1.00 144.63 C Atom 2623 NZ LYS A 605 55.175 0.314 27.861 1.00 135.22 N Atom 2624 C LYS A 605 60.210 1.981 27.180 1.00 137.38 C Atom 2625 O LYS A 605 60.948 2.478 28.031 1.00 135.56 O Atom 2626 N ASP A 606 59.179 2.633 26.649 1.00 140.81 N Atom 2627 CA ASP A 606 58.753 3.933 27.152 1.00 136.10 C Atom 2628 CB ASP A 606 57.610 4.489 26.303 1.00 130.54 C Atom 2629 CG ASP A 606 57.152 5.854 26.770 1.00 132.41 C Atom 2630 OD1 ASP A 606 57.989 6.780 26.818 1.00 135.66 O Atom 2631 OD2 ASP A 606 55.952 6.002 27.083 1.00 130.33 O Atom 2632 C ASP A 606 58.309 3.794 28.605 1.00 133.11 C Atom 2633 O ASP A 606 57.559 2.879 28.946 1.00 135.49 O Atom 2634 N MET A 607 58.765 4.707 29.456 1.00 128.88 N Atom 2635 CA MET A 607 58.566 4.563 30.896 1.00 126.19 C Atom 2636 CB MET A 607 59.910 4.661 31.622 1.00 123.39 C Atom 2637 CG MET A 607 60.857 3.514 31.318 1.00 127.66 C Atom 2638 SD MET A 607 60.198 1.926 31.861 1.00 132.30 S Atom 2639 CE MET A 607 60.048 2.211 33.624 1.00 119.39 C Atom 2640 C MET A 607 57.574 5.554 31.504 1.00 122.00 C Atom 2641 O MET A 607 57.277 5.482 32.697 1.00 120.28 O Atom 2642 N THR A 608 57.059 6.471 30.691 1.00 119.80 N Atom 2643 CA THR A 608 56.158 7.504 31.196 1.00 121.31 C Atom 2644 CB THR A 608 55.608 8.389 30.061 1.00 121.90 C Atom 2645 OG1 THR A 608 54.583 7.684 29.354 1.00 131.28 O Atom 2646 CG2 THR A 608 56.719 8.767 29.095 1.00 128.64 C Atom 2647 C THR A 608 54.990 6.906 31.979 1.00 119.72 C Atom 2648 O THR A 608 54.694 7.338 33.093 1.00 115.46 O Atom 2649 N LYS A 609 54.336 5.907 31.393 1.00 123.71 N Atom 2650 CA LYS A 609 53.199 5.260 32.039 1.00 123.09 C Atom 2651 CB LYS A 609 52.527 4.268 31.089 1.00 128.84 C Atom 2652 CG LYS A 609 51.856 4.918 29.888 1.00 138.20 C Atom 2653 CD LYS A 609 51.085 3.894 29.064 1.00 156.83 C Atom 2654 CE LYS A 609 52.004 2.810 28.518 1.00 155.77 C Atom 2655 NZ LYS A 609 51.270 1.851 27.647 1.00 159.00 N Atom 2656 C LYS A 609 53.621 4.560 33.325 1.00 109.50 C Atom 2657 O LYS A 609 53.021 4.765 34.378 1.00 107.67 O Atom 2658 N GLU A 610 54.655 3.731 33.231 1.00 112.30 N Atom 2659 CA GLU A 610 55.204 3.060 34.404 1.00 123.40 C Atom 2660 CB GLU A 610 56.548 2.413 34.065 1.00 128.02 C Atom 2661 CG GLU A 610 56.468 0.917 33.827 1.00 129.17 C Atom 2662 CD GLU A 610 56.428 0.132 35.124 1.00 132.80 C Atom 2663 OE1 GLU A 610 57.462 0.091 35.825 1.00 131.46 O Atom 2664 OE2 GLU A 610 55.366 −0.443 35.442 1.00 129.57 O Atom 2665 C GLU A 610 55.367 4.026 35.570 1.00 117.22 C Atom 2666 O GLU A 610 54.842 3.799 36.659 1.00 111.69 O Atom 2667 N PHE A 611 56.096 5.109 35.330 1.00 117.38 N Atom 2668 CA PHE A 611 56.354 6.103 36.363 1.00 114.82 C Atom 2669 CB PHE A 611 57.274 7.203 35.827 1.00 112.44 C Atom 2670 CG PHE A 611 58.697 6.763 35.622 1.00 115.09 C Atom 2671 CD1 PHE A 611 59.260 5.788 36.428 1.00 115.37 C Atom 2672 CE1 PHE A 611 60.571 5.390 36.244 1.00 114.85 C Atom 2673 CZ PHE A 611 61.337 5.976 35.260 1.00 112.48 C Atom 2674 CE2 PHE A 611 60.792 6.956 34.456 1.00 114.22 C Atom 2675 CD2 PHE A 611 59.481 7.347 34.641 1.00 113.55 C Atom 2676 C PHE A 611 55.069 6.717 36.923 1.00 106.27 C Atom 2677 O PHE A 611 54.755 6.560 38.105 1.00 102.31 O Atom 2678 N PHE A 612 54.330 7.414 36.069 1.00 98.04 N Atom 2679 CA PHE A 612 53.147 8.155 36.498 1.00 100.09 C Atom 2680 CB PHE A 612 52.600 8.982 35.334 1.00 107.30 C Atom 2681 CG PHE A 612 53.350 10.258 35.091 1.00 107.38 C Atom 2682 CD1 PHE A 612 53.138 11.363 35.900 1.00 104.26 C Atom 2683 CE1 PHE A 612 53.821 12.539 35.681 1.00 106.71 C Atom 2684 CZ PHE A 612 54.723 12.626 34.643 1.00 104.50 C Atom 2685 CE2 PHE A 612 54.942 11.538 33.826 1.00 108.95 C Atom 2686 CD2 PHE A 612 54.257 10.360 34.049 1.00 112.42 C Atom 2687 C PHE A 612 52.028 7.294 37.084 1.00 106.64 C Atom 2688 O PHE A 612 51.167 7.800 37.802 1.00 103.36 O Atom 2689 N GLU A 613 52.034 6.002 36.773 1.00 116.44 N Atom 2690 CA GLU A 613 50.959 5.118 37.215 1.00 108.38 C Atom 2691 CB GLU A 613 50.610 4.094 36.133 1.00 106.92 C Atom 2692 CG GLU A 613 50.059 4.723 34.865 1.00 105.69 C Atom 2693 CD GLU A 613 48.704 5.388 35.062 1.00 109.17 C Atom 2694 OE1 GLU A 613 48.019 5.085 36.060 1.00 99.41 O Atom 2695 OE2 GLU A 613 48.317 6.213 34.207 1.00 105.52 O Atom 2696 C GLU A 613 51.236 4.433 38.548 1.00 111.46 C Atom 2697 O GLU A 613 50.303 4.021 39.237 1.00 107.68 O Atom 2698 N ASN A 614 52.511 4.313 38.909 1.00 117.58 N Atom 2699 CA ASN A 614 52.867 3.792 40.227 1.00 121.99 C Atom 2700 CB ASN A 614 52.564 2.292 40.350 1.00 122.69 C Atom 2701 CG ASN A 614 53.117 1.483 39.197 1.00 132.57 C Atom 2702 OD1 ASN A 614 53.839 2.004 38.347 1.00 132.76 O Atom 2703 ND2 ASN A 614 52.784 0.197 39.165 1.00 128.04 N Atom 2704 C ASN A 614 54.281 4.109 40.714 1.00 128.90 C Atom 2705 O ASN A 614 54.587 5.256 41.038 1.00 113.22 O Atom 2706 N LYS A 615 55.134 3.092 40.771 1.00 138.63 N Atom 2707 CA LYS A 615 56.365 3.186 41.546 1.00 132.81 C Atom 2708 CB LYS A 615 56.595 1.894 42.336 1.00 139.62 C Atom 2709 CG LYS A 615 57.377 2.082 43.626 1.00 137.39 C Atom 2710 CD LYS A 615 56.686 1.368 44.780 1.00 141.88 C Atom 2711 CE LYS A 615 55.293 1.935 45.015 1.00 142.20 C Atom 2712 NZ LYS A 615 54.496 1.073 45.926 1.00 129.30 N Atom 2713 C LYS A 615 57.611 3.555 40.752 1.00 125.11 C Atom 2714 O LYS A 615 57.645 3.466 39.523 1.00 119.68 O Atom 2715 N SER A 616 58.631 3.937 41.513 1.00 125.44 N Atom 2716 CA SER A 616 59.881 4.525 41.049 1.00 120.83 C Atom 2717 CB SER A 616 59.853 4.895 39.569 1.00 114.99 C Atom 2718 OG SER A 616 61.170 5.112 39.096 1.00 112.57 O Atom 2719 C SER A 616 60.085 5.763 41.907 1.00 113.01 C Atom 2720 O SER A 616 60.681 6.752 41.477 1.00 101.80 O Atom 2721 N GLU A 617 59.537 5.697 43.120 1.00 116.89 N Atom 2722 CA GLU A 617 59.764 6.693 44.154 1.00 95.78 C Atom 2723 CB GLU A 617 58.915 6.368 45.385 1.00 104.09 C Atom 2724 CG GLU A 617 58.741 7.517 46.363 1.00 114.93 C Atom 2725 CD GLU A 617 57.550 7.326 47.286 1.00 119.59 C Atom 2726 OE1 GLU A 617 57.024 8.341 47.796 1.00 100.90 O Atom 2727 OE2 GLU A 617 57.135 6.164 47.491 1.00 121.26 O Atom 2728 C GLU A 617 61.234 6.604 44.505 1.00 98.91 C Atom 2729 O GLU A 617 61.608 6.561 45.677 1.00 100.44 O Atom 2730 N THR A 618 62.062 6.555 43.466 1.00 104.95 N Atom 2731 CA THR A 618 63.486 6.310 43.608 1.00 109.60 C Atom 2732 CB THR A 618 63.941 5.058 42.806 1.00 120.50 C Atom 2733 OG1 THR A 618 63.039 3.968 43.043 1.00 113.43 O Atom 2734 CG2 THR A 618 65.351 4.635 43.208 1.00 101.19 C Atom 2735 C THR A 618 64.267 7.530 43.140 1.00 105.00 C Atom 2736 O THR A 618 65.369 7.405 42.608 1.00 112.03 O Atom 2737 N TRP A 619 63.681 8.711 43.324 1.00 104.26 N Atom 2738 CA TRP A 619 64.406 9.961 43.118 1.00 92.89 C Atom 2739 CB TRP A 619 63.706 10.856 42.095 1.00 87.49 C Atom 2740 CG TRP A 619 62.956 10.134 41.028 1.00 98.62 C Atom 2741 CD1 TRP A 619 61.670 9.675 41.094 1.00 101.12 C Atom 2742 NE1 TRP A 619 61.321 9.078 39.910 1.00 100.83 N Atom 2743 CE2 TRP A 619 62.384 9.146 39.047 1.00 105.52 C Atom 2744 CD2 TRP A 619 63.431 9.811 39.718 1.00 99.40 C Atom 2745 CE3 TRP A 619 64.641 10.013 39.047 1.00 94.75 C Atom 2746 CZ3 TRP A 619 64.764 9.551 37.750 1.00 107.20 C Atom 2747 CH2 TRP A 619 63.703 8.895 37.110 1.00 115.63 C Atom 2748 CZ2 TRP A 619 62.508 8.683 37.741 1.00 104.22 C Atom 2749 C TRP A 619 64.497 10.706 44.443 1.00 83.55 C Atom 2750 O TRP A 619 63.474 11.054 45.030 1.00 85.63 O Atom 2751 N PRO A 620 65.722 10.937 44.930 1.00 82.79 N Atom 2752 CA PRO A 620 65.900 11.722 46.156 1.00 86.41 C Atom 2753 CB PRO A 620 67.412 11.658 46.396 1.00 84.36 C Atom 2754 CG PRO A 620 67.859 10.429 45.682 1.00 79.67 C Atom 2755 CD PRO A 620 66.984 10.335 44.469 1.00 82.65 C Atom 2756 C PRO A 620 65.449 13.174 45.981 1.00 78.86 C Atom 2757 O PRO A 620 65.775 13.815 44.981 1.00 75.82 O Atom 2758 N ILE A 621 64.692 13.669 46.955 1.00 78.76 N Atom 2759 CA ILE A 621 64.235 15.051 46.993 1.00 75.50 C Atom 2760 CB ILE A 621 62.834 15.197 46.377 1.00 78.06 C Atom 2761 CG1 ILE A 621 61.871 14.207 47.040 1.00 77.14 C Atom 2762 CD1 ILE A 621 60.412 14.528 46.829 1.00 88.15 C Atom 2763 CG2 ILE A 621 62.876 14.986 44.871 1.00 77.05 C Atom 2764 C ILE A 621 64.108 15.420 48.457 1.00 71.18 C Atom 2765 O ILE A 621 63.615 16.492 48.802 1.00 64.53 O Atom 2766 N GLY A 622 64.580 14.518 49.311 1.00 76.34 N Atom 2767 CA GLY A 622 64.140 14.464 50.691 1.00 81.76 C Atom 2768 C GLY A 622 64.830 15.299 51.744 1.00 70.85 C Atom 2769 O GLY A 622 64.752 16.522 51.722 1.00 78.29 O Atom 2770 N GLU A 623 65.478 14.616 52.683 1.00 74.86 N Atom 2771 CA GLU A 623 65.960 15.226 53.919 1.00 83.47 C Atom 2772 CB GLU A 623 66.675 16.554 53.656 1.00 95.20 C Atom 2773 CG GLU A 623 68.091 16.411 53.113 1.00 102.18 C Atom 2774 CD GLU A 623 69.069 15.870 54.144 1.00 97.18 C Atom 2775 OE1 GLU A 623 70.071 16.557 54.434 1.00 98.17 O Atom 2776 OE2 GLU A 623 68.831 14.764 54.673 1.00 96.44 O Atom 2777 C GLU A 623 64.821 15.414 54.919 1.00 91.51 C Atom 2778 O GLU A 623 63.989 16.310 54.772 1.00 81.01 O Atom 2779 N SER A 624 64.793 14.548 55.928 1.00 101.81 N Atom 2780 CA SER A 624 63.831 14.642 57.020 1.00 98.36 C Atom 2781 CB SER A 624 62.614 13.751 56.751 1.00 92.54 C Atom 2782 OG SER A 624 62.880 12.401 57.092 1.00 93.41 O Atom 2783 C SER A 624 64.539 14.208 58.301 1.00 94.52 C Atom 2784 O SER A 624 65.722 13.875 58.266 1.00 91.79 O Atom 2785 N PRO A 625 63.832 14.225 59.442 1.00 98.70 N Atom 2786 CA PRO A 625 64.479 13.732 60.663 1.00 103.15 C Atom 2787 CB PRO A 625 63.337 13.727 61.680 1.00 101.56 C Atom 2788 CG PRO A 625 62.438 14.819 61.220 1.00 93.59 C Atom 2789 CD PRO A 625 62.497 14.788 59.715 1.00 94.42 C Atom 2790 C PRO A 625 65.035 12.322 60.476 1.00 103.52 C Atom 2791 O PRO A 625 66.068 11.984 61.056 1.00 93.92 O Atom 2792 N LYS A 626 64.354 11.516 59.667 1.00 103.32 N Atom 2793 CA LYS A 626 64.799 10.159 59.369 1.00 100.47 C Atom 2794 CB LYS A 626 63.637 9.335 58.815 1.00 105.44 C Atom 2795 CG LYS A 626 62.413 9.333 59.712 1.00 112.03 C Atom 2796 CD LYS A 626 61.143 9.113 58.911 1.00 111.35 C Atom 2797 CE LYS A 626 59.911 9.484 59.723 1.00 124.64 C Atom 2798 NZ LYS A 626 58.705 9.645 58.860 1.00 129.01 N Atom 2799 C LYS A 626 65.959 10.166 58.377 1.00 94.40 C Atom 2800 O LYS A 626 66.637 9.155 58.195 1.00 99.11 O Atom 2801 N GLY A 627 66.179 11.310 57.735 1.00 94.71 N Atom 2802 CA GLY A 627 67.278 11.459 56.800 1.00 91.56 C Atom 2803 C GLY A 627 66.827 11.484 55.352 1.00 87.59 C Atom 2804 O GLY A 627 65.761 12.011 55.032 1.00 85.58 O Atom 2805 N MET A 628 67.650 10.911 54.479 1.00 93.82 N Atom 2806 CA MET A 628 67.359 10.851 53.052 1.00 90.56 C Atom 2807 CB MET A 628 68.311 9.874 52.359 1.00 102.34 C Atom 2808 CG MET A 628 67.977 9.594 50.901 1.00 100.31 C Atom 2809 SD MET A 628 68.039 11.082 49.888 1.00 101.81 S Atom 2810 CE MET A 628 69.647 11.720 50.352 1.00 84.99 C Atom 2811 C MET A 628 65.915 10.442 52.796 1.00 91.86 C Atom 2812 O MET A 628 65.396 9.528 53.437 1.00 90.16 O Atom 2813 N GLU A 629 65.272 11.127 51.856 1.00 91.03 N Atom 2814 CA GLU A 629 63.884 10.842 51.515 1.00 86.38 C Atom 2815 CB GLU A 629 62.953 11.838 52.209 1.00 80.15 C Atom 2816 CG GLU A 629 61.562 11.299 52.464 1.00 100.60 C Atom 2817 CD GLU A 629 61.562 10.166 53.473 1.00 100.76 C Atom 2818 OE1 GLU A 629 62.112 10.356 54.580 1.00 94.06 O Atom 2819 OE2 GLU A 629 61.012 9.089 53.158 1.00 101.39 O Atom 2820 C GLU A 629 63.680 10.879 50.000 1.00 86.26 C Atom 2821 O GLU A 629 64.340 11.641 49.294 1.00 89.17 O Atom 2822 N GLU A 630 62.768 10.051 49.501 1.00 86.58 N Atom 2823 CA GLU A 630 62.543 9.958 48.061 1.00 87.17 C Atom 2824 CB GLU A 630 63.101 8.643 47.514 1.00 90.56 C Atom 2825 CG GLU A 630 64.572 8.421 47.830 1.00 92.59 C Atom 2826 CD GLU A 630 65.177 7.294 47.018 1.00 94.36 C Atom 2827 OE1 GLU A 630 64.468 6.742 46.153 1.00 93.27 O Atom 2828 OE2 GLU A 630 66.361 6.963 47.241 1.00 96.04 O Atom 2829 C GLU A 630 61.070 10.108 47.693 1.00 87.88 C Atom 2830 O GLU A 630 60.187 9.907 48.526 1.00 88.40 O Atom 2831 N GLY A 631 60.814 10.469 46.439 1.00 84.64 N Atom 2832 CA GLY A 631 59.461 10.710 45.972 1.00 85.80 C Atom 2833 C GLY A 631 59.288 10.358 44.509 1.00 82.95 C Atom 2834 O GLY A 631 60.259 10.326 43.752 1.00 84.40 O Atom 2835 N SER A 632 58.047 10.096 44.109 1.00 83.13 N Atom 2836 CA SER A 632 57.753 9.710 42.733 1.00 90.06 C Atom 2837 CB SER A 632 56.410 8.974 42.647 1.00 88.29 C Atom 2838 OG SER A 632 55.332 9.802 43.055 1.00 86.18 O Atom 2839 C SER A 632 57.765 10.904 41.782 1.00 82.07 C Atom 2840 O SER A 632 57.793 12.056 42.211 1.00 83.75 O Atom 2841 N ILE A 633 57.744 10.606 40.487 1.00 83.46 N Atom 2842 CA ILE A 633 57.751 11.613 39.431 1.00 86.57 C Atom 2843 CB ILE A 633 57.431 10.977 38.065 1.00 86.62 C Atom 2844 CG1 ILE A 633 57.688 9.469 38.106 1.00 103.94 C Atom 2845 CD1 ILE A 633 56.628 8.679 38.859 1.00 103.79 C Atom 2846 CG2 ILE A 633 58.226 11.657 36.954 1.00 82.97 C Atom 2847 C ILE A 633 56.732 12.714 39.689 1.00 85.17 C Atom 2848 O ILE A 633 56.929 13.862 39.291 1.00 79.59 O Atom 2849 N GLY A 634 55.634 12.352 40.345 1.00 82.80 N Atom 2850 CA GLY A 634 54.610 13.315 40.695 1.00 78.65 C Atom 2851 C GLY A 634 55.187 14.444 41.525 1.00 83.48 C Atom 2852 O GLY A 634 55.094 15.615 41.153 1.00 76.88 O Atom 2853 N LYS A 635 55.792 14.085 42.653 1.00 79.86 N Atom 2854 CA LYS A 635 56.434 15.058 43.528 1.00 80.73 C Atom 2855 CB LYS A 635 56.955 14.375 44.795 1.00 79.34 C Atom 2856 CG LYS A 635 55.858 13.717 45.617 1.00 95.76 C Atom 2857 CD LYS A 635 56.398 13.019 46.851 1.00 104.62 C Atom 2858 CE LYS A 635 55.266 12.405 47.659 1.00 97.56 C Atom 2859 NZ LYS A 635 55.777 11.672 48.846 1.00 102.49 N Atom 2860 C LYS A 635 57.566 15.762 42.793 1.00 77.12 C Atom 2861 O LYS A 635 57.777 16.962 42.962 1.00 80.79 O Atom 2862 N VAL A 636 58.285 15.010 41.967 1.00 76.00 N Atom 2863 CA VAL A 636 59.370 15.574 41.174 1.00 79.36 C Atom 2864 CB VAL A 636 60.089 14.494 40.343 1.00 80.70 C Atom 2865 CG1 VAL A 636 61.185 15.113 39.492 1.00 79.41 C Atom 2866 CG2 VAL A 636 60.669 13.427 41.253 1.00 82.27 C Atom 2867 C VAL A 636 58.852 16.671 40.247 1.00 77.23 C Atom 2868 O VAL A 636 59.450 17.742 40.145 1.00 77.82 O Atom 2869 N CYS A 637 57.738 16.398 39.576 1.00 72.19 N Atom 2870 CA CYS A 637 57.118 17.380 38.696 1.00 72.42 C Atom 2871 CB CYS A 637 55.795 16.848 38.142 1.00 81.75 C Atom 2872 SG CYS A 637 55.962 15.549 36.901 1.00 81.50 S Atom 2873 C CYS A 637 56.867 18.684 39.441 1.00 74.97 C Atom 2874 O CYS A 637 57.181 19.766 38.945 1.00 74.57 O Atom 2875 N ARG A 638 56.300 18.572 40.638 1.00 75.11 N Atom 2876 CA ARG A 638 55.965 19.743 41.440 1.00 71.66 C Atom 2877 CB ARG A 638 55.025 19.361 42.586 1.00 71.75 C Atom 2878 CG ARG A 638 53.595 19.091 42.148 1.00 72.75 C Atom 2879 CD ARG A 638 52.700 18.758 43.333 1.00 72.70 C Atom 2880 NE ARG A 638 53.052 17.481 43.948 1.00 78.15 N Atom 2881 CZ ARG A 638 52.618 16.301 43.517 1.00 82.05 C Atom 2882 NH1 ARG A 638 51.816 16.235 42.463 1.00 73.50 N Atom 2883 NH2 ARG A 638 52.988 15.188 44.137 1.00 76.52 N Atom 2884 C ARG A 638 57.212 20.434 41.982 1.00 71.12 C Atom 2885 O ARG A 638 57.308 21.660 41.959 1.00 71.75 O Atom 2886 N THR A 639 58.163 19.645 42.468 1.00 69.12 N Atom 2887 CA THR A 639 59.407 20.193 42.996 1.00 69.30 C Atom 2888 CB THR A 639 60.331 19.090 43.531 1.00 68.02 C Atom 2889 OG1 THR A 639 59.717 18.465 44.665 1.00 71.55 O Atom 2890 CG2 THR A 639 61.667 19.677 43.950 1.00 65.50 C Atom 2891 C THR A 639 60.149 21.012 41.945 1.00 70.35 C Atom 2892 O THR A 639 60.624 22.111 42.227 1.00 70.09 O Atom 2893 N LEU A 640 60.243 20.477 40.733 1.00 69.36 N Atom 2894 CA LEU A 640 60.910 21.186 39.647 1.00 66.39 C Atom 2895 CB LEU A 640 61.148 20.259 38.453 1.00 71.48 C Atom 2896 CG LEU A 640 62.232 19.200 38.670 1.00 71.92 C Atom 2897 CD1 LEU A 640 62.571 18.496 37.367 1.00 72.87 C Atom 2898 CD2 LEU A 640 63.469 19.838 39.269 1.00 64.54 C Atom 2899 C LEU A 640 60.116 22.415 39.221 1.00 68.97 C Atom 2900 O LEU A 640 60.690 23.421 38.806 1.00 73.04 O Atom 2901 N LEU A 641 58.794 22.336 39.328 1.00 68.65 N Atom 2902 CA LEU A 641 57.950 23.479 39.013 1.00 66.96 C Atom 2903 CB LEU A 641 56.472 23.091 39.064 1.00 66.75 C Atom 2904 CG LEU A 641 55.513 23.832 38.129 1.00 66.15 C Atom 2905 CD1 LEU A 641 54.169 24.030 38.813 1.00 67.27 C Atom 2906 CD2 LEU A 641 56.082 25.170 37.699 1.00 66.47 C Atom 2907 C LEU A 641 58.236 24.583 40.022 1.00 66.42 C Atom 2908 O LEU A 641 58.482 25.731 39.654 1.00 66.34 O Atom 2909 N ALA A 642 58.213 24.217 41.300 1.00 65.72 N Atom 2910 CA ALA A 642 58.482 25.158 42.378 1.00 62.38 C Atom 2911 CB ALA A 642 58.409 24.457 43.726 1.00 59.78 C Atom 2912 C ALA A 642 59.843 25.820 42.190 1.00 63.52 C Atom 2913 O ALA A 642 59.970 27.039 42.303 1.00 63.41 O Atom 2914 N LYS A 643 60.858 25.015 41.892 1.00 60.01 N Atom 2915 CA LYS A 643 62.199 25.542 41.676 1.00 63.46 C Atom 2916 CB LYS A 643 63.192 24.414 41.388 1.00 64.77 C Atom 2917 CG LYS A 643 64.624 24.891 41.206 1.00 64.07 C Atom 2918 CD LYS A 643 65.579 23.734 40.994 1.00 72.85 C Atom 2919 CE LYS A 643 67.018 24.223 40.908 1.00 88.23 C Atom 2920 NZ LYS A 643 67.987 23.089 40.808 1.00 95.20 N Atom 2921 C LYS A 643 62.217 26.563 40.542 1.00 63.06 C Atom 2922 O LYS A 643 62.759 27.658 40.688 1.00 59.19 O Atom 2923 N SER A 644 61.624 26.198 39.412 1.00 61.31 N Atom 2924 CA SER A 644 61.550 27.103 38.274 1.00 60.12 C Atom 2925 CB SER A 644 60.851 26.423 37.100 1.00 63.23 C Atom 2926 OG SER A 644 60.749 27.303 35.996 1.00 64.44 O Atom 2927 C SER A 644 60.813 28.388 38.639 1.00 61.74 C Atom 2928 O SER A 644 61.195 29.479 38.210 1.00 63.14 O Atom 2929 N VAL A 645 59.759 28.252 39.438 1.00 63.43 N Atom 2930 CA VAL A 645 58.943 29.396 39.833 1.00 63.72 C Atom 2931 CB VAL A 645 57.592 28.955 40.434 1.00 59.72 C Atom 2932 CG1 VAL A 645 56.908 30.119 41.132 1.00 58.83 C Atom 2933 CG2 VAL A 645 56.696 28.394 39.350 1.00 59.71 C Atom 2934 C VAL A 645 59.675 30.320 40.804 1.00 62.52 C Atom 2935 O VAL A 645 59.617 31.542 40.669 1.00 60.59 O Atom 2936 N PHE A 646 60.364 29.737 41.779 1.00 58.88 N Atom 2937 CA PHE A 646 61.130 30.527 42.737 1.00 61.38 C Atom 2938 CB PHE A 646 61.567 29.671 43.928 1.00 61.48 C Atom 2939 CG PHE A 646 60.567 29.646 45.050 1.00 62.87 C Atom 2940 CD1 PHE A 646 59.227 29.399 44.796 1.00 59.06 C Atom 2941 CE1 PHE A 646 58.304 29.377 45.825 1.00 55.39 C Atom 2942 CZ PHE A 646 58.714 29.600 47.124 1.00 56.74 C Atom 2943 CE2 PHE A 646 60.047 29.846 47.391 1.00 61.33 C Atom 2944 CD2 PHE A 646 60.966 29.869 46.357 1.00 62.52 C Atom 2945 C PHE A 646 62.327 31.215 42.084 1.00 61.29 C Atom 2946 O PHE A 646 62.699 32.322 42.473 1.00 57.57 O Atom 2947 N ASN A 647 62.926 30.558 41.094 1.00 60.55 N Atom 2948 CA ASN A 647 63.975 31.179 40.293 1.00 58.77 C Atom 2949 CB ASN A 647 64.430 30.242 39.172 1.00 59.08 C Atom 2950 CG ASN A 647 65.358 29.145 39.663 1.00 64.13 C Atom 2951 OD1 ASN A 647 66.006 29.279 40.701 1.00 62.43 O Atom 2952 ND2 ASN A 647 65.429 28.052 38.912 1.00 60.93 N Atom 2953 C ASN A 647 63.463 32.478 39.690 1.00 65.02 C Atom 2954 O ASN A 647 64.186 33.471 39.608 1.00 64.78 O Atom 2955 N SER A 648 62.202 32.460 39.273 1.00 65.94 N Atom 2956 CA SER A 648 61.583 33.612 38.636 1.00 60.36 C Atom 2957 CB SER A 648 60.416 33.154 37.760 1.00 61.55 C Atom 2958 OG SER A 648 59.943 34.204 36.934 1.00 75.70 O Atom 2959 C SER A 648 61.111 34.628 39.674 1.00 63.54 C Atom 2960 O SER A 648 61.266 35.837 39.492 1.00 65.43 O Atom 2961 N LEU A 649 60.531 34.125 40.761 1.00 64.30 N Atom 2962 CA LEU A 649 60.052 34.968 41.853 1.00 61.15 C Atom 2963 CB LEU A 649 59.292 34.124 42.878 1.00 62.86 C Atom 2964 CG LEU A 649 57.764 34.237 42.928 1.00 62.79 C Atom 2965 CD1 LEU A 649 57.173 34.671 41.592 1.00 57.76 C Atom 2966 CD2 LEU A 649 57.154 32.928 43.409 1.00 55.59 C Atom 2967 C LEU A 649 61.192 35.699 42.545 1.00 60.41 C Atom 2968 O LEU A 649 61.031 36.827 43.006 1.00 62.41 O Atom 2969 N TYR A 650 62.345 35.047 42.621 1.00 63.70 N Atom 2970 CA TYR A 650 63.491 35.610 43.319 1.00 61.27 C Atom 2971 CB TYR A 650 63.933 34.678 44.447 1.00 57.52 C Atom 2972 CG TYR A 650 62.976 34.623 45.615 1.00 58.29 C Atom 2973 CD1 TYR A 650 62.933 35.647 46.549 1.00 57.96 C Atom 2974 CE1 TYR A 650 62.064 35.598 47.620 1.00 61.03 C Atom 2975 CZ TYR A 650 61.222 34.514 47.768 1.00 57.15 C Atom 2976 OH TYR A 650 60.355 34.463 48.835 1.00 54.15 O Atom 2977 CE2 TYR A 650 61.245 33.484 46.853 1.00 54.41 C Atom 2978 CD2 TYR A 650 62.118 33.545 45.785 1.00 58.37 C Atom 2979 C TYR A 650 64.659 35.876 42.376 1.00 63.59 C Atom 2980 O TYR A 650 65.820 35.789 42.774 1.00 57.87 O Atom 2981 N ALA A 651 64.341 36.202 41.127 1.00 64.11 N Atom 2982 CA ALA A 651 65.359 36.524 40.136 1.00 60.08 C Atom 2983 CB ALA A 651 64.715 36.957 38.833 1.00 56.28 C Atom 2984 C ALA A 651 66.284 37.612 40.661 1.00 59.28 C Atom 2985 O ALA A 651 65.827 38.629 41.184 1.00 60.12 O Atom 2986 N SER A 652 67.587 37.388 40.522 1.00 59.07 N Atom 2987 CA SER A 652 68.587 38.343 40.991 1.00 58.06 C Atom 2988 CB SER A 652 68.642 38.346 42.521 1.00 59.23 C Atom 2989 OG SER A 652 69.205 37.143 43.015 1.00 58.66 O Atom 2990 C SER A 652 69.965 38.026 40.425 1.00 62.03 C Atom 2991 O SER A 652 70.233 36.887 40.042 1.00 60.36 O Atom 2992 N PRO A 653 70.841 39.041 40.359 1.00 66.59 N Atom 2993 CA PRO A 653 72.217 38.822 39.910 1.00 58.66 C Atom 2994 CB PRO A 653 72.881 40.173 40.161 1.00 53.15 C Atom 2995 CG PRO A 653 71.776 41.155 40.078 1.00 54.73 C Atom 2996 CD PRO A 653 70.574 40.460 40.654 1.00 55.28 C Atom 2997 C PRO A 653 72.890 37.745 40.752 1.00 59.06 C Atom 2998 O PRO A 653 73.609 36.908 40.205 1.00 64.74 O Atom 2999 N GLN A 654 72.664 37.773 42.063 1.00 58.52 N Atom 3000 CA GLN A 654 73.182 36.735 42.942 1.00 61.85 C Atom 3001 CB GLN A 654 72.654 36.915 44.369 1.00 63.51 C Atom 3002 CG GLN A 654 73.029 38.236 45.025 1.00 73.74 C Atom 3003 CD GLN A 654 72.883 38.212 46.539 1.00 73.50 C Atom 3004 OE1 GLN A 654 73.093 37.182 47.179 1.00 71.84 O Atom 3005 NE2 GLN A 654 72.515 39.352 47.117 1.00 63.19 N Atom 3006 C GLN A 654 72.826 35.349 42.418 1.00 64.18 C Atom 3007 O GLN A 654 73.642 34.432 42.463 1.00 62.30 O Atom 3008 N LEU A 655 71.609 35.210 41.903 1.00 62.33 N Atom 3009 CA LEU A 655 71.124 33.923 41.415 1.00 59.28 C Atom 3010 CB LEU A 655 69.599 33.928 41.298 1.00 55.72 C Atom 3011 CG LEU A 655 68.994 32.586 40.874 1.00 56.39 C Atom 3012 CD1 LEU A 655 69.362 31.502 41.876 1.00 47.93 C Atom 3013 CD2 LEU A 655 67.483 32.693 40.710 1.00 59.18 C Atom 3014 C LEU A 655 71.750 33.522 40.080 1.00 61.75 C Atom 3015 O LEU A 655 72.129 32.367 39.886 1.00 60.05 O Atom 3016 N GLU A 656 71.848 34.475 39.158 1.00 61.63 N Atom 3017 CA GLU A 656 72.492 34.226 37.872 1.00 64.30 C Atom 3018 CB GLU A 656 72.567 35.509 37.041 1.00 62.62 C Atom 3019 CG GLU A 656 71.227 36.017 36.540 1.00 79.67 C Atom 3020 CD GLU A 656 70.583 35.081 35.528 1.00 102.95 C Atom 3021 OE1 GLU A 656 70.608 35.412 34.323 1.00 116.88 O Atom 3022 OE2 GLU A 656 70.056 34.018 35.932 1.00 91.78 O Atom 3023 C GLU A 656 73.894 33.671 38.093 1.00 65.94 C Atom 3024 O GLU A 656 74.286 32.670 37.487 1.00 60.53 O Atom 3025 N GLY A 657 74.640 34.332 38.972 1.00 57.60 N Atom 3026 CA GLY A 657 75.987 33.914 39.301 1.00 54.55 C Atom 3027 C GLY A 657 76.023 32.526 39.902 1.00 61.31 C Atom 3028 O GLY A 657 76.693 31.636 39.380 1.00 68.52 O Atom 3029 N PHE A 658 75.296 32.336 40.997 1.00 62.01 N Atom 3030 CA PHE A 658 75.282 31.050 41.682 1.00 58.64 C Atom 3031 CB PHE A 658 74.253 31.039 42.811 1.00 55.83 C Atom 3032 CG PHE A 658 74.223 29.752 43.588 1.00 57.46 C Atom 3033 CD1 PHE A 658 75.154 29.510 44.584 1.00 54.25 C Atom 3034 CE1 PHE A 658 75.132 28.327 45.301 1.00 55.72 C Atom 3035 CZ PHE A 658 74.173 27.371 45.023 1.00 54.07 C Atom 3036 CE2 PHE A 658 73.241 27.601 44.030 1.00 53.64 C Atom 3037 CD2 PHE A 658 73.269 28.783 43.318 1.00 56.83 C Atom 3038 C PHE A 658 74.999 29.902 40.721 1.00 62.90 C Atom 3039 O PHE A 658 75.731 28.922 40.689 1.00 61.96 O Atom 3040 N SER A 659 73.931 30.025 39.943 1.00 64.10 N Atom 3041 CA SER A 659 73.559 28.976 39.002 1.00 61.50 C Atom 3042 CB SER A 659 72.361 29.415 38.166 1.00 61.78 C Atom 3043 OG SER A 659 71.251 29.680 38.998 1.00 72.63 O Atom 3044 C SER A 659 74.715 28.598 38.086 1.00 63.74 C Atom 3045 O SER A 659 75.131 27.441 38.039 1.00 65.61 O Atom 3046 N ALA A 660 75.227 29.582 37.356 1.00 64.22 N Atom 3047 CA ALA A 660 76.322 29.356 36.422 1.00 59.50 C Atom 3048 CB ALA A 660 76.765 30.670 35.802 1.00 51.21 C Atom 3049 C ALA A 660 77.503 28.659 37.094 1.00 67.57 C Atom 3050 O ALA A 660 78.070 27.710 36.550 1.00 65.55 O Atom 3051 N GLU A 661 77.860 29.127 38.285 1.00 62.70 N Atom 3052 CA GLU A 661 79.049 28.634 38.970 1.00 64.02 C Atom 3053 CB GLU A 661 79.598 29.701 39.920 1.00 66.60 C Atom 3054 CG GLU A 661 79.868 31.044 39.255 1.00 65.59 C Atom 3055 CD GLU A 661 80.949 30.975 38.187 1.00 70.61 C Atom 3056 OE1 GLU A 661 81.463 29.869 37.913 1.00 66.72 O Atom 3057 OE2 GLU A 661 81.287 32.035 37.620 1.00 73.32 O Atom 3058 C GLU A 661 78.815 27.329 39.727 1.00 60.69 C Atom 3059 O GLU A 661 79.688 26.462 39.758 1.00 67.75 O Atom 3060 N SER A 662 77.644 27.192 40.339 1.00 61.85 N Atom 3061 CA SER A 662 77.330 25.997 41.116 1.00 61.18 C Atom 3062 CB SER A 662 76.087 26.223 41.979 1.00 56.20 C Atom 3063 OG SER A 662 74.962 26.536 41.177 1.00 56.79 O Atom 3064 C SER A 662 77.132 24.783 40.214 1.00 62.28 C Atom 3065 O SER A 662 77.280 23.643 40.654 1.00 64.49 O Atom 3066 N ARG A 663 76.794 25.032 38.953 1.00 62.49 N Atom 3067 CA ARG A 663 76.634 23.958 37.983 1.00 63.87 C Atom 3068 CB ARG A 663 76.152 24.514 36.643 1.00 68.01 C Atom 3069 CG ARG A 663 74.996 23.735 36.038 1.00 84.65 C Atom 3070 CD ARG A 663 74.780 24.088 34.575 1.00 95.92 C Atom 3071 NE ARG A 663 75.415 23.118 33.689 1.00 113.53 N Atom 3072 CZ ARG A 663 74.857 21.971 33.316 1.00 122.79 C Atom 3073 NH1 ARG A 663 73.646 21.650 33.752 1.00 120.58 N Atom 3074 NH2 ARG A 663 75.510 21.146 32.508 1.00 118.60 N Atom 3075 C ARG A 663 77.973 23.255 37.799 1.00 69.19 C Atom 3076 O ARG A 663 78.042 22.026 37.745 1.00 71.18 O Atom 3077 N LYS A 664 79.037 24.047 37.711 1.00 61.51 N Atom 3078 CA LYS A 664 80.382 23.516 37.545 1.00 65.02 C Atom 3079 CB LYS A 664 81.381 24.659 37.375 1.00 63.63 C Atom 3080 CG LYS A 664 81.069 25.574 36.202 1.00 61.36 C Atom 3081 CD LYS A 664 81.915 26.834 36.254 1.00 63.21 C Atom 3082 CE LYS A 664 81.517 27.809 35.158 1.00 65.95 C Atom 3083 NZ LYS A 664 82.294 29.079 35.231 1.00 67.00 N Atom 3084 C LYS A 664 80.780 22.636 38.727 1.00 68.51 C Atom 3085 O LYS A 664 81.252 21.516 38.545 1.00 68.67 O Atom 3086 N LEU A 665 80.589 23.149 39.938 1.00 62.00 N Atom 3087 CA LEU A 665 80.899 22.386 41.140 1.00 64.90 C Atom 3088 CB LEU A 665 80.653 23.225 42.398 1.00 64.14 C Atom 3089 CG LEU A 665 81.069 22.569 43.719 1.00 64.67 C Atom 3090 CD1 LEU A 665 82.511 22.087 43.642 1.00 63.54 C Atom 3091 CD2 LEU A 665 80.876 23.518 44.895 1.00 59.06 C Atom 3092 C LEU A 665 80.068 21.110 41.178 1.00 69.51 C Atom 3093 O LEU A 665 80.530 20.068 41.642 1.00 70.20 O Atom 3094 N LEU A 666 78.838 21.203 40.684 1.00 68.16 N Atom 3095 CA LEU A 666 77.956 20.049 40.606 1.00 68.69 C Atom 3096 CB LEU A 666 76.579 20.475 40.094 1.00 70.39 C Atom 3097 CG LEU A 666 75.534 19.371 39.923 1.00 73.79 C Atom 3098 CD1 LEU A 666 75.140 18.798 41.277 1.00 72.63 C Atom 3099 CD2 LEU A 666 74.315 19.893 39.180 1.00 70.22 C Atom 3100 C LEU A 666 78.559 18.979 39.696 1.00 74.76 C Atom 3101 O LEU A 666 78.663 17.811 40.073 1.00 73.02 O Atom 3102 N LEU A 667 78.959 19.390 38.498 1.00 72.17 N Atom 3103 CA LEU A 667 79.630 18.494 37.562 1.00 70.83 C Atom 3104 CB LEU A 667 80.089 19.262 36.321 1.00 66.80 C Atom 3105 CG LEU A 667 79.001 19.667 35.325 1.00 69.37 C Atom 3106 CD1 LEU A 667 79.606 20.450 34.171 1.00 69.60 C Atom 3107 CD2 LEU A 667 78.261 18.443 34.814 1.00 70.30 C Atom 3108 C LEU A 667 80.829 17.829 38.226 1.00 69.76 C Atom 3109 O LEU A 667 80.961 16.604 38.211 1.00 72.39 O Atom 3110 N ILE A 668 81.694 18.650 38.813 1.00 68.83 N Atom 3111 CA ILE A 668 82.904 18.165 39.469 1.00 68.97 C Atom 3112 CB ILE A 668 83.730 19.327 40.047 1.00 68.90 C Atom 3113 CG1 ILE A 668 84.376 20.133 38.916 1.00 68.74 C Atom 3114 CD1 ILE A 668 84.894 21.484 39.345 1.00 66.70 C Atom 3115 CG2 ILE A 668 84.787 18.803 40.999 1.00 66.79 C Atom 3116 C ILE A 668 82.587 17.167 40.578 1.00 74.15 C Atom 3117 O ILE A 668 83.238 16.129 40.693 1.00 78.81 O Atom 3118 N VAL A 669 81.584 17.482 41.392 1.00 72.53 N Atom 3119 CA VAL A 669 81.198 16.607 42.494 1.00 73.04 C Atom 3120 CB VAL A 669 80.123 17.249 43.395 1.00 68.56 C Atom 3121 CG1 VAL A 669 79.559 16.224 44.364 1.00 74.51 C Atom 3122 CG2 VAL A 669 80.711 18.415 44.156 1.00 72.01 C Atom 3123 C VAL A 669 80.708 15.252 41.992 1.00 75.66 C Atom 3124 O VAL A 669 81.023 14.217 42.576 1.00 78.09 O Atom 3125 N GLN A 670 79.941 15.262 40.906 1.00 74.75 N Atom 3126 CA GLN A 670 79.438 14.023 40.324 1.00 76.59 C Atom 3127 CB GLN A 670 78.433 14.313 39.204 1.00 75.76 C Atom 3128 CG GLN A 670 77.049 14.698 39.706 1.00 77.85 C Atom 3129 CD GLN A 670 75.990 14.617 38.623 1.00 79.73 C Atom 3130 OE1 GLN A 670 76.295 14.689 37.433 1.00 80.66 O Atom 3131 NE2 GLN A 670 74.735 14.465 39.032 1.00 79.12 N Atom 3132 C GLN A 670 80.579 13.146 39.815 1.00 81.31 C Atom 3133 O GLN A 670 80.582 11.932 40.028 1.00 83.93 O Atom 3134 N ALA A 671 81.549 13.765 39.148 1.00 83.81 N Atom 3135 CA ALA A 671 82.709 13.043 38.637 1.00 79.81 C Atom 3136 CB ALA A 671 83.633 13.984 37.877 1.00 72.69 C Atom 3137 C ALA A 671 83.460 12.348 39.769 1.00 81.01 C Atom 3138 O ALA A 671 83.608 11.125 39.768 1.00 81.26 O Atom 3139 N LEU A 672 83.927 13.136 40.734 1.00 80.61 N Atom 3140 CA LEU A 672 84.636 12.596 41.890 1.00 85.30 C Atom 3141 CB LEU A 672 84.931 13.704 42.905 1.00 80.80 C Atom 3142 CG LEU A 672 85.965 14.757 42.501 1.00 84.86 C Atom 3143 CD1 LEU A 672 86.123 15.802 43.596 1.00 81.94 C Atom 3144 CD2 LEU A 672 87.302 14.105 42.187 1.00 84.51 C Atom 3145 C LEU A 672 83.843 11.475 42.556 1.00 87.91 C Atom 3146 O LEU A 672 84.409 10.472 42.990 1.00 86.74 O Atom 3147 N ARG A 673 82.528 11.655 42.630 1.00 84.29 N Atom 3148 CA ARG A 673 81.640 10.670 43.236 1.00 87.98 C Atom 3149 CB ARG A 673 80.205 11.209 43.265 1.00 84.37 C Atom 3150 CG ARG A 673 79.140 10.215 43.706 1.00 78.01 C Atom 3151 CD ARG A 673 77.849 10.946 44.049 1.00 82.47 C Atom 3152 NE ARG A 673 76.653 10.203 43.658 1.00 86.49 N Atom 3153 CZ ARG A 673 75.917 9.469 44.488 1.00 85.29 C Atom 3154 NH1 ARG A 673 76.252 9.368 45.768 1.00 78.29 N Atom 3155 NH2 ARG A 673 74.843 8.834 44.036 1.00 78.65 N Atom 3156 C ARG A 673 81.707 9.327 42.506 1.00 90.89 C Atom 3157 O ARG A 673 81.533 8.269 43.114 1.00 84.19 O Atom 3158 N ASP A 674 81.968 9.374 41.203 1.00 85.70 N Atom 3159 CA ASP A 674 82.071 8.159 40.400 1.00 88.22 C Atom 3160 CB ASP A 674 81.453 8.371 39.016 1.00 88.66 C Atom 3161 CG ASP A 674 79.944 8.513 39.064 1.00 102.99 C Atom 3162 OD1 ASP A 674 79.245 7.583 38.606 1.00 110.95 O Atom 3163 OD2 ASP A 674 79.456 9.549 39.565 1.00 98.78 O Atom 3164 C ASP A 674 83.517 7.704 40.245 1.00 93.78 C Atom 3165 O ASP A 674 83.829 6.880 39.383 1.00 93.53 O Atom 3166 N ASN A 675 84.397 8.242 41.082 1.00 91.45 N Atom 3167 CA ASN A 675 85.820 7.947 40.975 1.00 95.06 C Atom 3168 CB ASN A 675 86.077 6.456 41.193 1.00 96.01 C Atom 3169 CG ASN A 675 85.748 6.013 42.601 1.00 107.05 C Atom 3170 OD1 ASN A 675 86.321 6.513 43.568 1.00 107.61 O Atom 3171 ND2 ASN A 675 84.826 5.062 42.725 1.00 107.91 N Atom 3172 C ASN A 675 86.396 8.391 39.633 1.00 93.25 C Atom 3173 O ASN A 675 87.052 7.614 38.938 1.00 91.97 O Atom 3174 N LEU A 676 86.140 9.646 39.275 1.00 87.12 N Atom 3175 CA LEU A 676 86.687 10.228 38.054 1.00 90.86 C Atom 3176 CB LEU A 676 85.578 10.517 37.040 1.00 86.32 C Atom 3177 CG LEU A 676 85.337 9.456 35.964 1.00 86.09 C Atom 3178 CD1 LEU A 676 84.806 8.172 36.575 1.00 86.75 C Atom 3179 CD2 LEU A 676 84.382 9.988 34.908 1.00 88.17 C Atom 3180 C LEU A 676 87.467 11.504 38.341 1.00 88.47 C Atom 3181 O LEU A 676 87.023 12.355 39.111 1.00 90.16 O Atom 3182 N GLU A 677 88.634 11.629 37.719 1.00 89.29 N Atom 3183 CA GLU A 677 89.447 12.828 37.857 1.00 84.99 C Atom 3184 CB GLU A 677 90.922 12.506 37.596 1.00 81.49 C Atom 3185 CG GLU A 677 91.820 13.727 37.483 1.00 77.52 C Atom 3186 CD GLU A 677 91.859 14.540 38.762 1.00 82.35 C Atom 3187 OE1 GLU A 677 91.722 15.780 38.681 1.00 71.67 O Atom 3188 OE2 GLU A 677 92.016 13.936 39.846 1.00 84.39 O Atom 3189 C GLU A 677 88.961 13.898 36.887 1.00 81.18 C Atom 3190 O GLU A 677 89.053 13.722 35.668 1.00 80.32 O Atom 3191 N PRO A 678 88.433 15.007 37.427 1.00 71.70 N Atom 3192 CA PRO A 678 87.978 16.143 36.620 1.00 73.21 C Atom 3193 CB PRO A 678 87.430 17.122 37.665 1.00 71.47 C Atom 3194 CG PRO A 678 87.160 16.293 38.876 1.00 77.35 C Atom 3195 CD PRO A 678 88.228 15.242 38.865 1.00 76.99 C Atom 3196 C PRO A 678 89.141 16.784 35.876 1.00 74.10 C Atom 3197 O PRO A 678 88.941 17.357 34.807 1.00 74.63 O Atom 3198 N GLY A 679 90.341 16.686 36.437 1.00 68.68 N Atom 3199 CA GLY A 679 91.513 17.279 35.824 1.00 67.50 C Atom 3200 C GLY A 679 92.055 18.424 36.654 1.00 67.31 C Atom 3201 O GLY A 679 91.453 18.825 37.649 1.00 61.89 O Atom 3202 N THR A 680 93.204 18.951 36.250 1.00 62.89 N Atom 3203 CA THR A 680 93.778 20.104 36.929 1.00 64.47 C Atom 3204 CB THR A 680 95.218 20.368 36.476 1.00 62.30 C Atom 3205 OG1 THR A 680 96.027 19.233 36.811 1.00 58.02 O Atom 3206 CG2 THR A 680 95.768 21.601 37.176 1.00 54.44 C Atom 3207 C THR A 680 92.914 21.352 36.741 1.00 62.14 C Atom 3208 O THR A 680 92.886 21.963 35.670 1.00 57.00 O Atom 3209 N PHE A 681 92.210 21.719 37.805 1.00 65.30 N Atom 3210 CA PHE A 681 91.247 22.807 37.761 1.00 62.48 C Atom 3211 CB PHE A 681 89.836 22.229 37.602 1.00 62.48 C Atom 3212 CG PHE A 681 88.739 23.241 37.745 1.00 66.71 C Atom 3213 CD1 PHE A 681 88.417 24.083 36.696 1.00 67.70 C Atom 3214 CE1 PHE A 681 87.403 25.011 36.823 1.00 64.74 C Atom 3215 CZ PHE A 681 86.697 25.099 38.004 1.00 62.21 C Atom 3216 CE2 PHE A 681 87.007 24.260 39.056 1.00 63.72 C Atom 3217 CD2 PHE A 681 88.017 23.338 38.923 1.00 65.13 C Atom 3218 C PHE A 681 91.359 23.621 39.044 1.00 58.11 C Atom 3219 O PHE A 681 91.503 23.059 40.129 1.00 59.48 O Atom 3220 N ASP A 682 91.313 24.944 38.919 1.00 56.69 N Atom 3221 CA ASP A 682 91.410 25.816 40.084 1.00 58.15 C Atom 3222 CB ASP A 682 91.721 27.251 39.661 1.00 58.40 C Atom 3223 CG ASP A 682 91.996 28.155 40.843 1.00 64.16 C Atom 3224 OD1 ASP A 682 92.233 27.624 41.950 1.00 62.24 O Atom 3225 OD2 ASP A 682 91.976 29.393 40.669 1.00 67.23 O Atom 3226 C ASP A 682 90.121 25.769 40.905 1.00 60.14 C Atom 3227 O ASP A 682 89.313 26.699 40.869 1.00 60.25 O Atom 3228 N LEU A 683 89.940 24.680 41.645 1.00 62.74 N Atom 3229 CA LEU A 683 88.726 24.465 42.422 1.00 62.74 C Atom 3230 CB LEU A 683 88.810 23.136 43.173 1.00 61.54 C Atom 3231 CG LEU A 683 87.524 22.332 43.336 1.00 65.82 C Atom 3232 CD1 LEU A 683 87.651 21.379 44.511 1.00 69.08 C Atom 3233 CD2 LEU A 683 86.334 23.253 43.522 1.00 65.31 C Atom 3234 C LEU A 683 88.503 25.610 43.404 1.00 61.70 C Atom 3235 O LEU A 683 87.411 26.171 43.482 1.00 66.14 O Atom 3236 N GLY A 684 89.542 25.947 44.160 1.00 61.01 N Atom 3237 CA GLY A 684 89.457 27.025 45.125 1.00 53.85 C Atom 3238 C GLY A 684 88.970 28.298 44.470 1.00 58.46 C Atom 3239 O GLY A 684 88.204 29.062 45.058 1.00 61.28 O Atom 3240 N GLY A 685 89.417 28.523 43.240 1.00 58.53 N Atom 3241 CA GLY A 685 88.989 29.676 42.472 1.00 57.88 C Atom 3242 C GLY A 685 87.497 29.627 42.225 1.00 58.33 C Atom 3243 O GLY A 685 86.808 30.639 42.334 1.00 61.10 O Atom 3244 N LEU A 686 87.001 28.438 41.894 1.00 59.54 N Atom 3245 CA LEU A 686 85.570 28.218 41.698 1.00 58.70 C Atom 3246 CB LEU A 686 85.299 26.770 41.291 1.00 58.31 C Atom 3247 CG LEU A 686 83.840 26.383 41.044 1.00 59.77 C Atom 3248 CD1 LEU A 686 83.258 27.159 39.872 1.00 59.53 C Atom 3249 CD2 LEU A 686 83.730 24.889 40.801 1.00 60.93 C Atom 3250 C LEU A 686 84.780 28.554 42.958 1.00 61.53 C Atom 3251 O LEU A 686 83.743 29.211 42.890 1.00 60.35 O Atom 3252 N TYR A 687 85.269 28.093 44.105 1.00 59.65 N Atom 3253 CA TYR A 687 84.626 28.394 45.381 1.00 63.73 C Atom 3254 CB TYR A 687 85.355 27.712 46.539 1.00 56.94 C Atom 3255 CG TYR A 687 84.824 26.333 46.851 1.00 61.29 C Atom 3256 CD1 TYR A 687 84.098 26.091 48.010 1.00 64.52 C Atom 3257 CE1 TYR A 687 83.608 24.829 48.296 1.00 66.97 C Atom 3258 CZ TYR A 687 83.840 23.793 47.414 1.00 67.79 C Atom 3259 OH TYR A 687 83.360 22.534 47.685 1.00 66.16 O Atom 3260 CE2 TYR A 687 84.555 24.010 46.257 1.00 68.05 C Atom 3261 CD2 TYR A 687 85.040 25.273 45.980 1.00 68.02 C Atom 3262 C TYR A 687 84.514 29.898 45.627 1.00 63.14 C Atom 3263 O TYR A 687 83.505 30.372 46.155 1.00 66.02 O Atom 3264 N GLU A 688 85.544 30.648 45.249 1.00 60.64 N Atom 3265 CA GLU A 688 85.494 32.101 45.373 1.00 68.44 C Atom 3266 CB GLU A 688 86.774 32.744 44.839 1.00 72.34 C Atom 3267 CG GLU A 688 87.902 32.846 45.840 1.00 74.42 C Atom 3268 CD GLU A 688 88.874 33.955 45.490 1.00 95.92 C Atom 3269 OE1 GLU A 688 90.097 33.696 45.460 1.00 114.90 O Atom 3270 OE2 GLU A 688 88.410 35.088 45.238 1.00 92.00 O Atom 3271 C GLU A 688 84.302 32.640 44.601 1.00 67.38 C Atom 3272 O GLU A 688 83.483 33.385 45.134 1.00 67.24 O Atom 3273 N ALA A 689 84.215 32.249 43.335 1.00 63.37 N Atom 3274 CA ALA A 689 83.140 32.703 42.466 1.00 65.20 C Atom 3275 CB ALA A 689 83.246 32.030 41.107 1.00 58.93 C Atom 3276 C ALA A 689 81.769 32.445 43.087 1.00 67.79 C Atom 3277 O ALA A 689 80.914 33.328 43.121 1.00 70.41 O Atom 3278 N ILE A 690 81.570 31.227 43.578 1.00 62.78 N Atom 3279 CA ILE A 690 80.295 30.832 44.159 1.00 60.72 C Atom 3280 CB ILE A 690 80.263 29.319 44.460 1.00 60.50 C Atom 3281 CG1 ILE A 690 80.284 28.513 43.161 1.00 63.23 C Atom 3282 CD1 ILE A 690 80.313 27.019 43.378 1.00 58.23 C Atom 3283 CG2 ILE A 690 79.039 28.968 45.283 1.00 64.01 C Atom 3284 C ILE A 690 79.969 31.611 45.435 1.00 66.36 C Atom 3285 O ILE A 690 78.882 32.179 45.568 1.00 64.52 O Atom 3286 N GLU A 691 80.920 31.650 46.363 1.00 64.85 N Atom 3287 CA GLU A 691 80.680 32.239 47.676 1.00 62.59 C Atom 3288 CB GLU A 691 81.755 31.782 48.664 1.00 59.82 C Atom 3289 CG GLU A 691 81.718 30.280 48.924 1.00 66.77 C Atom 3290 CD GLU A 691 82.889 29.780 49.748 1.00 72.58 C Atom 3291 OE1 GLU A 691 83.938 30.458 49.766 1.00 72.93 O Atom 3292 OE2 GLU A 691 82.760 28.703 50.372 1.00 68.50 O Atom 3293 C GLU A 691 80.566 33.762 47.651 1.00 64.79 C Atom 3294 O GLU A 691 80.195 34.382 48.649 1.00 59.86 O Atom 3295 N GLU A 692 80.874 34.363 46.508 1.00 64.37 N Atom 3296 CA GLU A 692 80.743 35.806 46.362 1.00 65.92 C Atom 3297 CB GLU A 692 81.793 36.351 45.395 1.00 66.86 C Atom 3298 CG GLU A 692 81.476 36.110 43.934 1.00 78.93 C Atom 3299 CD GLU A 692 82.657 36.402 43.027 1.00 97.65 C Atom 3300 OE1 GLU A 692 82.590 36.037 41.833 1.00 101.43 O Atom 3301 OE2 GLU A 692 83.654 36.987 43.509 1.00 91.71 O Atom 3302 C GLU A 692 79.341 36.157 45.880 1.00 66.71 C Atom 3303 O GLU A 692 78.954 37.327 45.851 1.00 69.99 O Atom 3304 N CYS A 693 78.584 35.133 45.501 1.00 62.00 N Atom 3305 CA CYS A 693 77.187 35.312 45.128 1.00 62.95 C Atom 3306 CB CYS A 693 76.782 34.316 44.045 1.00 66.93 C Atom 3307 SG CYS A 693 77.694 34.462 42.507 1.00 65.01 S Atom 3308 C CYS A 693 76.306 35.109 46.349 1.00 63.50 C Atom 3309 O CYS A 693 75.108 35.392 46.319 1.00 65.65 O Atom 3310 N LEU A 694 76.913 34.607 47.420 1.00 58.29 N Atom 3311 CA LEU A 694 76.204 34.350 48.665 1.00 61.63 C Atom 3312 CB LEU A 694 76.744 33.087 49.332 1.00 59.55 C Atom 3313 CG LEU A 694 76.909 31.877 48.415 1.00 59.76 C Atom 3314 CD1 LEU A 694 77.622 30.739 49.133 1.00 61.76 C Atom 3315 CD2 LEU A 694 75.559 31.425 47.891 1.00 60.62 C Atom 3316 C LEU A 694 76.349 35.536 49.605 1.00 65.19 C Atom 3317 O LEU A 694 77.255 35.576 50.436 1.00 70.59 O Atom 3318 N ILE A 695 75.443 36.497 49.471 1.00 73.26 N Atom 3319 CA ILE A 695 75.521 37.729 50.241 1.00 71.50 C Atom 3320 CB ILE A 695 75.610 38.952 49.317 1.00 71.86 C Atom 3321 CG1 ILE A 695 76.686 38.734 48.249 1.00 62.87 C Atom 3322 CD1 ILE A 695 76.610 39.703 47.090 1.00 61.87 C Atom 3323 CG2 ILE A 695 75.886 40.204 50.129 1.00 73.24 C Atom 3324 C ILE A 695 74.336 37.897 51.190 1.00 72.44 C Atom 3325 O ILE A 695 74.515 37.917 52.408 1.00 73.41 O Atom 3326 N ASN A 696 73.132 38.018 50.636 1.00 69.68 N Atom 3327 CA ASN A 696 71.948 38.260 51.457 1.00 69.08 C Atom 3328 CB ASN A 696 71.843 39.748 51.809 1.00 71.94 C Atom 3329 CG ASN A 696 71.705 40.629 50.585 1.00 72.17 C Atom 3330 OD1 ASN A 696 71.214 40.195 49.544 1.00 70.89 O Atom 3331 ND2 ASN A 696 72.133 41.881 50.708 1.00 73.83 N Atom 3332 C ASN A 696 70.621 37.765 50.872 1.00 66.51 C Atom 3333 O ASN A 696 69.592 37.814 51.545 1.00 73.05 O Atom 3334 N ASP A 697 70.635 37.293 49.629 1.00 63.12 N Atom 3335 CA ASP A 697 69.407 36.804 49.006 1.00 60.56 C Atom 3336 CB ASP A 697 69.573 36.670 47.490 1.00 60.40 C Atom 3337 CG ASP A 697 68.281 36.269 46.796 1.00 64.21 C Atom 3338 OD1 ASP A 697 67.888 35.087 46.894 1.00 59.57 O Atom 3339 OD2 ASP A 697 67.657 37.137 46.149 1.00 67.35 O Atom 3340 C ASP A 697 68.969 35.477 49.621 1.00 68.18 C Atom 3341 O ASP A 697 69.735 34.514 49.645 1.00 65.45 O Atom 3342 N PRO A 698 67.722 35.423 50.112 1.00 63.60 N Atom 3343 CA PRO A 698 67.208 34.254 50.834 1.00 57.14 C Atom 3344 CB PRO A 698 65.805 34.694 51.261 1.00 63.47 C Atom 3345 CG PRO A 698 65.426 35.765 50.313 1.00 59.83 C Atom 3346 CD PRO A 698 66.688 36.447 49.888 1.00 60.66 C Atom 3347 C PRO A 698 67.124 33.026 49.937 1.00 55.66 C Atom 3348 O PRO A 698 67.408 31.916 50.386 1.00 60.67 O Atom 3349 N TRP A 699 66.731 33.229 48.684 1.00 56.03 N Atom 3350 CA TRP A 699 66.596 32.133 47.730 1.00 58.65 C Atom 3351 CB TRP A 699 65.861 32.620 46.479 1.00 54.60 C Atom 3352 CG TRP A 699 65.741 31.608 45.376 1.00 55.91 C Atom 3353 CD1 TRP A 699 66.099 31.778 44.069 1.00 56.28 C Atom 3354 NE1 TRP A 699 65.829 30.638 43.356 1.00 58.01 N Atom 3355 CE2 TRP A 699 65.291 29.705 44.193 1.00 60.41 C Atom 3356 CD2 TRP A 699 65.216 30.276 45.480 1.00 58.98 C Atom 3357 CE3 TRP A 699 64.696 29.517 46.531 1.00 58.96 C Atom 3358 CZ3 TRP A 699 64.272 28.226 46.270 1.00 57.92 C Atom 3359 CH2 TRP A 699 64.358 27.681 44.981 1.00 58.42 C Atom 3360 CZ2 TRP A 699 64.862 28.402 43.935 1.00 58.41 C Atom 3361 C TRP A 699 67.954 31.533 47.375 1.00 61.69 C Atom 3362 O TRP A 699 68.118 30.314 47.350 1.00 60.04 O Atom 3363 N VAL A 700 68.929 32.398 47.118 1.00 59.89 N Atom 3364 CA VAL A 700 70.280 31.952 46.798 1.00 57.40 C Atom 3365 CB VAL A 700 71.183 33.125 46.381 1.00 57.40 C Atom 3366 CG1 VAL A 700 72.644 32.717 46.429 1.00 58.80 C Atom 3367 CG2 VAL A 700 70.803 33.599 44.994 1.00 58.90 C Atom 3368 C VAL A 700 70.911 31.217 47.973 1.00 58.18 C Atom 3369 O VAL A 700 71.527 30.165 47.797 1.00 60.76 O Atom 3370 N LEU A 701 70.749 31.768 49.171 1.00 57.55 N Atom 3371 CA LEU A 701 71.298 31.145 50.369 1.00 58.45 C Atom 3372 CB LEU A 701 71.029 32.006 51.605 1.00 61.34 C Atom 3373 CG LEU A 701 71.683 33.391 51.638 1.00 61.58 C Atom 3374 CD1 LEU A 701 71.370 34.110 52.943 1.00 64.29 C Atom 3375 CD2 LEU A 701 73.177 33.270 51.441 1.00 60.34 C Atom 3376 C LEU A 701 70.722 29.747 50.566 1.00 60.08 C Atom 3377 O LEU A 701 71.424 28.835 51.000 1.00 60.76 O Atom 3378 N LEU A 702 69.444 29.578 50.240 1.00 59.28 N Atom 3379 CA LEU A 702 68.809 28.274 50.363 1.00 60.73 C Atom 3380 CB LEU A 702 67.317 28.357 50.039 1.00 59.33 C Atom 3381 CG LEU A 702 66.408 27.404 50.822 1.00 57.87 C Atom 3382 CD1 LEU A 702 65.124 27.137 50.052 1.00 59.56 C Atom 3383 CD2 LEU A 702 67.113 26.101 51.140 1.00 56.02 C Atom 3384 C LEU A 702 69.495 27.283 49.430 1.00 62.03 C Atom 3385 O LEU A 702 69.933 26.215 49.860 1.00 61.49 O Atom 3386 N ASN A 703 69.587 27.644 48.152 1.00 60.25 N Atom 3387 CA ASN A 703 70.250 26.794 47.170 1.00 61.68 C Atom 3388 CB ASN A 703 70.246 27.454 45.790 1.00 58.28 C Atom 3389 CG ASN A 703 68.878 27.428 45.139 1.00 62.35 C Atom 3390 OD1 ASN A 703 67.935 28.042 45.634 1.00 63.21 O Atom 3391 ND2 ASN A 703 68.764 26.720 44.020 1.00 65.89 N Atom 3392 C ASN A 703 71.671 26.436 47.592 1.00 61.09 C Atom 3393 O ASN A 703 72.138 25.320 47.361 1.00 59.56 O Atom 3394 N ALA A 704 72.354 27.388 48.219 1.00 57.01 N Atom 3395 CA ALA A 704 73.685 27.134 48.748 1.00 57.97 C Atom 3396 CB ALA A 704 74.288 28.409 49.302 1.00 57.75 C Atom 3397 C ALA A 704 73.610 26.060 49.827 1.00 62.69 C Atom 3398 O ALA A 704 74.324 25.060 49.779 1.00 63.44 O Atom 3399 N SER A 705 72.732 26.271 50.800 1.00 60.44 N Atom 3400 CA SER A 705 72.515 25.291 51.853 1.00 60.45 C Atom 3401 CB SER A 705 71.424 25.770 52.810 1.00 61.00 C Atom 3402 OG SER A 705 71.231 24.848 53.866 1.00 55.16 O Atom 3403 C SER A 705 72.128 23.945 51.255 1.00 62.72 C Atom 3404 O SER A 705 72.596 22.899 51.705 1.00 64.15 O Atom 3405 N TRP A 706 71.267 23.977 50.242 1.00 60.80 N Atom 3406 CA TRP A 706 70.858 22.761 49.552 1.00 64.21 C Atom 3407 CB TRP A 706 69.900 23.077 48.402 1.00 62.40 C Atom 3408 CG TRP A 706 68.478 23.240 48.820 1.00 61.10 C Atom 3409 CD1 TRP A 706 67.924 22.859 50.006 1.00 58.93 C Atom 3410 NE1 TRP A 706 66.585 23.161 50.020 1.00 58.63 N Atom 3411 CE2 TRP A 706 66.245 23.730 48.822 1.00 59.93 C Atom 3412 CD2 TRP A 706 67.413 23.792 48.037 1.00 62.64 C Atom 3413 CE3 TRP A 706 67.337 24.340 46.752 1.00 62.31 C Atom 3414 CZ3 TRP A 706 66.114 24.800 46.301 1.00 64.31 C Atom 3415 CH2 TRP A 706 64.969 24.723 47.106 1.00 60.82 C Atom 3416 CZ2 TRP A 706 65.015 24.193 48.365 1.00 59.31 C Atom 3417 C TRP A 706 72.073 22.024 49.013 1.00 64.99 C Atom 3418 O TRP A 706 72.214 20.815 49.198 1.00 65.26 O Atom 3419 N PHE A 707 72.953 22.761 48.344 1.00 66.07 N Atom 3420 CA PHE A 707 74.142 22.163 47.753 1.00 64.70 C Atom 3421 CB PHE A 707 74.972 23.205 47.005 1.00 64.65 C Atom 3422 CG PHE A 707 75.986 22.610 46.075 1.00 70.54 C Atom 3423 CD1 PHE A 707 75.689 22.425 44.736 1.00 73.11 C Atom 3424 CE1 PHE A 707 76.619 21.876 43.876 1.00 75.15 C Atom 3425 CZ PHE A 707 77.860 21.503 44.352 1.00 75.00 C Atom 3426 CE2 PHE A 707 78.167 21.680 45.687 1.00 74.91 C Atom 3427 CD2 PHE A 707 77.234 22.231 46.540 1.00 70.28 C Atom 3428 C PHE A 707 74.988 21.486 48.823 1.00 62.37 C Atom 3429 O PHE A 707 75.434 20.355 48.643 1.00 66.37 O Atom 3430 N ASN A 708 75.200 22.178 49.938 1.00 59.11 N Atom 3431 CA ASN A 708 75.928 21.601 51.061 1.00 60.54 C Atom 3432 CB ASN A 708 75.906 22.546 52.261 1.00 61.84 C Atom 3433 CG ASN A 708 76.827 23.731 52.084 1.00 66.96 C Atom 3434 OD1 ASN A 708 77.665 23.751 51.182 1.00 68.18 O Atom 3435 ND2 ASN A 708 76.679 24.729 52.947 1.00 67.56 N Atom 3436 C ASN A 708 75.367 20.244 51.469 1.00 66.65 C Atom 3437 O ASN A 708 76.116 19.309 51.742 1.00 68.63 O Atom 3438 N SER A 709 74.044 20.145 51.519 1.00 70.30 N Atom 3439 CA SER A 709 73.389 18.892 51.862 1.00 68.96 C Atom 3440 CB SER A 709 71.890 19.110 52.034 1.00 70.81 C Atom 3441 OG SER A 709 71.647 20.016 53.093 1.00 79.36 O Atom 3442 C SER A 709 73.647 17.844 50.792 1.00 74.03 C Atom 3443 O SER A 709 73.984 16.700 51.097 1.00 79.79 O Atom 3444 N PHE A 710 73.483 18.238 49.535 1.00 68.35 N Atom 3445 CA PHE A 710 73.797 17.351 48.427 1.00 69.99 C Atom 3446 CB PHE A 710 73.579 18.050 47.087 1.00 68.85 C Atom 3447 CG PHE A 710 74.328 17.417 45.948 1.00 73.78 C Atom 3448 CD1 PHE A 710 73.918 16.206 45.420 1.00 70.84 C Atom 3449 CE1 PHE A 710 74.602 15.624 44.372 1.00 70.98 C Atom 3450 CZ PHE A 710 75.708 16.249 43.838 1.00 71.43 C Atom 3451 CE2 PHE A 710 76.129 17.458 44.354 1.00 75.76 C Atom 3452 CD2 PHE A 710 75.441 18.036 45.403 1.00 73.62 C Atom 3453 C PHE A 710 75.242 16.899 48.534 1.00 75.14 C Atom 3454 O PHE A 710 75.551 15.723 48.362 1.00 77.90 O Atom 3455 N LEU A 711 76.121 17.850 48.830 1.00 74.79 N Atom 3456 CA LEU A 711 77.552 17.597 48.936 1.00 74.05 C Atom 3457 CB LEU A 711 78.281 18.903 49.256 1.00 72.39 C Atom 3458 CG LEU A 711 79.798 18.942 49.084 1.00 80.54 C Atom 3459 CD1 LEU A 711 80.514 18.480 50.346 1.00 81.37 C Atom 3460 CD2 LEU A 711 80.217 18.120 47.874 1.00 83.76 C Atom 3461 C LEU A 711 77.864 16.539 49.990 1.00 79.37 C Atom 3462 O LEU A 711 78.759 15.712 49.808 1.00 78.54 O Atom 3463 N THR A 712 77.120 16.568 51.090 1.00 78.56 N Atom 3464 CA THR A 712 77.324 15.619 52.179 1.00 82.46 C Atom 3465 CB THR A 712 76.541 16.028 53.441 1.00 78.38 C Atom 3466 OG1 THR A 712 76.939 17.343 53.848 1.00 85.11 O Atom 3467 CG2 THR A 712 76.808 15.050 54.577 1.00 82.04 C Atom 3468 C THR A 712 76.929 14.196 51.788 1.00 86.69 C Atom 3469 O THR A 712 77.633 13.238 52.109 1.00 90.13 O Atom 3470 N HIS A 713 75.800 14.063 51.099 1.00 79.95 N Atom 3471 CA HIS A 713 75.318 12.755 50.665 1.00 82.60 C Atom 3472 CB HIS A 713 73.828 12.811 50.306 1.00 79.75 C Atom 3473 CG HIS A 713 72.929 13.039 51.484 1.00 83.19 C Atom 3474 ND1 HIS A 713 72.553 12.028 52.337 1.00 84.33 N Atom 3475 CE1 HIS A 713 71.763 12.521 53.279 1.00 86.30 C Atom 3476 NE2 HIS A 713 71.618 13.813 53.063 1.00 86.12 N Atom 3477 CD2 HIS A 713 72.336 14.167 51.945 1.00 82.55 C Atom 3478 C HIS A 713 76.121 12.228 49.479 1.00 82.76 C Atom 3479 O HIS A 713 76.391 11.031 49.382 1.00 85.23 O Atom 3480 N ALA A 714 76.503 13.131 48.583 1.00 82.45 N Atom 3481 CA ALA A 714 77.200 12.756 47.358 1.00 82.03 C Atom 3482 CB ALA A 714 77.296 13.950 46.414 1.00 78.13 C Atom 3483 C ALA A 714 78.586 12.183 47.635 1.00 80.85 C Atom 3484 O ALA A 714 79.032 11.258 46.956 1.00 76.31 O Atom 3485 N LEU A 715 79.264 12.737 48.634 1.00 83.07 N Atom 3486 CA LEU A 715 80.619 12.312 48.963 1.00 79.99 C Atom 3487 CB LEU A 715 81.603 13.463 48.750 1.00 79.40 C Atom 3488 CG LEU A 715 81.595 14.019 47.325 1.00 75.95 C Atom 3489 CD1 LEU A 715 82.396 15.306 47.240 1.00 77.40 C Atom 3490 CD2 LEU A 715 82.115 12.985 46.337 1.00 77.43 C Atom 3491 C LEU A 715 80.705 11.770 50.387 1.00 89.14 C Atom 3492 O LEU A 715 81.691 11.989 51.094 1.00 91.74 O Atom 3493 N LYS A 716 79.656 11.061 50.794 1.00 97.46 N Atom 3494 CA LYS A 716 79.626 10.389 52.085 1.00 101.58 C Atom 3495 CB LYS A 716 78.294 9.659 52.271 1.00 100.90 C Atom 3496 CG LYS A 716 77.900 9.402 53.719 1.00 110.27 C Atom 3497 CD LYS A 716 77.045 10.536 54.264 1.00 112.85 C Atom 3498 CE LYS A 716 76.372 10.140 55.571 1.00 115.02 C Atom 3499 NZ LYS A 716 75.375 11.153 56.025 1.00 106.15 N Atom 3500 C LYS A 716 80.764 9.382 52.141 1.00 111.23 C Atom 3501 O LYS A 716 80.807 8.442 51.345 1.00 108.00 O Atom 3502 OXT LYS A 716 81.660 9.485 52.978 1.00 117.50 O TER 3502 LYS A 716 Atom 3503 N GLU B 1 59.386 16.266 59.073 1.00 105.40 N Atom 3504 CA GLU B 1 58.684 16.408 57.803 1.00 108.01 C Atom 3505 CB GLU B 1 57.561 17.439 57.924 1.00 106.22 C Atom 3506 CG GLU B 1 56.829 17.717 56.619 1.00 108.44 C Atom 3507 CD GLU B 1 56.054 16.513 56.102 1.00 116.84 C Atom 3508 OE1 GLU B 1 56.633 15.407 56.023 1.00 108.99 O Atom 3509 OE2 GLU B 1 54.861 16.679 55.768 1.00 126.59 O Atom 3510 C GLU B 1 59.638 16.791 56.673 1.00 101.83 C Atom 3511 O GLU B 1 60.427 17.730 56.804 1.00 96.26 O Atom 3512 N THR B 2 59.549 16.059 55.565 1.00 93.31 N Atom 3513 CA THR B 2 60.446 16.233 54.422 1.00 87.24 C Atom 3514 CB THR B 2 59.977 15.395 53.200 1.00 84.73 C Atom 3515 OG1 THR B 2 60.680 15.804 52.019 1.00 73.01 O Atom 3516 CG2 THR B 2 58.490 15.569 52.972 1.00 102.09 C Atom 3517 C THR B 2 60.623 17.691 54.001 1.00 88.55 C Atom 3518 O THR B 2 59.710 18.304 53.447 1.00 85.14 O Atom 3519 N ASP B 3 61.802 18.242 54.281 1.00 84.43 N Atom 3520 CA ASP B 3 62.196 19.531 53.727 1.00 69.27 C Atom 3521 CB ASP B 3 63.288 20.178 54.582 1.00 64.77 C Atom 3522 CG ASP B 3 62.732 20.908 55.790 1.00 77.08 C Atom 3523 OD1 ASP B 3 61.500 21.108 55.849 1.00 83.83 O Atom 3524 OD2 ASP B 3 63.525 21.286 56.678 1.00 71.04 O Atom 3525 C ASP B 3 62.705 19.320 52.304 1.00 69.46 C Atom 3526 O ASP B 3 63.811 18.826 52.106 1.00 72.37 O Atom 3527 N VAL B 4 61.895 19.693 51.318 1.00 72.01 N Atom 3528 CA VAL B 4 62.232 19.462 49.915 1.00 67.73 C Atom 3529 CB VAL B 4 61.132 20.002 48.986 1.00 67.67 C Atom 3530 CG1 VAL B 4 61.331 19.497 47.561 1.00 63.35 C Atom 3531 CG2 VAL B 4 59.764 19.606 49.512 1.00 57.85 C Atom 3532 C VAL B 4 63.571 20.083 49.523 1.00 66.16 C Atom 3533 O VAL B 4 63.878 21.213 49.907 1.00 66.02 O Atom 3534 N ASN B 5 64.358 19.334 48.755 1.00 65.98 N Atom 3535 CA ASN B 5 65.660 19.791 48.283 1.00 58.21 C Atom 3536 CB ASN B 5 66.757 19.340 49.252 1.00 61.91 C Atom 3537 CG ASN B 5 68.153 19.744 48.798 1.00 65.96 C Atom 3538 OD1 ASN B 5 68.357 20.164 47.660 1.00 65.79 O Atom 3539 ND2 ASN B 5 69.122 19.612 49.696 1.00 63.88 N Atom 3540 C ASN B 5 65.938 19.246 46.884 1.00 60.38 C Atom 3541 O ASN B 5 66.437 18.130 46.742 1.00 68.53 O Atom 3542 N PRO B 6 65.625 20.039 45.846 1.00 59.71 N Atom 3543 CA PRO B 6 65.745 19.637 44.437 1.00 62.86 C Atom 3544 CB PRO B 6 65.365 20.914 43.674 1.00 61.61 C Atom 3545 CG PRO B 6 64.590 21.732 44.641 1.00 62.59 C Atom 3546 CD PRO B 6 65.193 21.440 45.979 1.00 61.75 C Atom 3547 C PRO B 6 67.159 19.201 44.036 1.00 66.27 C Atom 3548 O PRO B 6 67.311 18.394 43.119 1.00 71.17 O Atom 3549 N THR B 7 68.178 19.733 44.700 1.00 63.94 N Atom 3550 CA THR B 7 69.554 19.412 44.340 1.00 67.51 C Atom 3551 CB THR B 7 70.559 20.309 45.085 1.00 65.64 C Atom 3552 OG1 THR B 7 70.077 21.658 45.094 1.00 60.72 O Atom 3553 CG2 THR B 7 71.920 20.266 44.399 1.00 63.60 C Atom 3554 C THR B 7 69.865 17.943 44.613 1.00 70.20 C Atom 3555 O THR B 7 70.740 17.356 43.978 1.00 72.49 O Atom 3556 N LEU B 8 69.132 17.352 45.551 1.00 70.58 N Atom 3557 CA LEU B 8 69.311 15.944 45.885 1.00 71.88 C Atom 3558 CB LEU B 8 68.424 15.548 47.066 1.00 71.26 C Atom 3559 CG LEU B 8 68.798 16.163 48.414 1.00 73.26 C Atom 3560 CD1 LEU B 8 67.979 15.535 49.529 1.00 73.88 C Atom 3561 CD2 LEU B 8 70.288 15.998 48.682 1.00 72.04 C Atom 3562 C LEU B 8 69.024 15.039 44.690 1.00 72.29 C Atom 3563 O LEU B 8 69.517 13.914 44.623 1.00 74.23 O Atom 3564 N LEU B 9 68.223 15.532 43.752 1.00 70.54 N Atom 3565 CA LEU B 9 67.935 14.792 42.530 1.00 71.50 C Atom 3566 CB LEU B 9 67.087 15.637 41.577 1.00 68.34 C Atom 3567 CG LEU B 9 65.587 15.719 41.859 1.00 73.85 C Atom 3568 CD1 LEU B 9 64.943 16.824 41.035 1.00 66.07 C Atom 3569 CD2 LEU B 9 64.926 14.379 41.580 1.00 77.82 C Atom 3570 C LEU B 9 69.226 14.388 41.835 1.00 75.42 C Atom 3571 O LEU B 9 69.289 13.352 41.177 1.00 76.80 O Atom 3572 N PHE B 10 70.255 15.216 41.986 1.00 75.59 N Atom 3573 CA PHE B 10 71.525 14.986 41.309 1.00 76.72 C Atom 3574 CB PHE B 10 72.332 16.281 41.207 1.00 71.34 C Atom 3575 CG PHE B 10 71.725 17.292 40.282 1.00 72.28 C Atom 3576 CD1 PHE B 10 71.321 18.529 40.751 1.00 67.94 C Atom 3577 CE1 PHE B 10 70.757 19.456 39.900 1.00 70.77 C Atom 3578 CZ PHE B 10 70.583 19.148 38.565 1.00 70.71 C Atom 3579 CE2 PHE B 10 70.977 17.915 38.087 1.00 77.67 C Atom 3580 CD2 PHE B 10 71.541 16.995 38.943 1.00 72.56 C Atom 3581 C PHE B 10 72.349 13.880 41.962 1.00 77.38 C Atom 3582 O PHE B 10 73.487 13.628 41.564 1.00 78.94 O Atom 3583 N LEU B 11 71.771 13.228 42.965 1.00 76.01 N Atom 3584 CA LEU B 11 72.348 12.010 43.514 1.00 73.01 C Atom 3585 CB LEU B 11 71.741 11.689 44.877 1.00 68.05 C Atom 3586 CG LEU B 11 72.230 12.509 46.069 1.00 70.96 C Atom 3587 CD1 LEU B 11 71.301 12.318 47.257 1.00 70.50 C Atom 3588 CD2 LEU B 11 73.667 12.149 46.435 1.00 74.24 C Atom 3589 C LEU B 11 72.064 10.869 42.550 1.00 78.78 C Atom 3590 O LEU B 11 72.720 9.828 42.587 1.00 84.89 O Atom 3591 N LYS B 12 71.079 11.082 41.683 1.00 75.69 N Atom 3592 CA LYS B 12 70.657 10.069 40.727 1.00 76.24 C Atom 3593 CB LYS B 12 69.248 9.580 41.069 1.00 83.41 C Atom 3594 CG LYS B 12 68.763 8.402 40.242 1.00 89.64 C Atom 3595 CD LYS B 12 67.821 7.535 41.059 1.00 96.46 C Atom 3596 CE LYS B 12 67.164 6.454 40.213 1.00 107.15 C Atom 3597 NZ LYS B 12 66.047 6.980 39.375 1.00 100.69 N Atom 3598 C LYS B 12 70.708 10.611 39.301 1.00 78.83 C Atom 3599 O LYS B 12 71.258 9.973 38.406 1.00 81.06 O Atom 3600 N VAL B 13 70.132 11.791 39.096 1.00 81.70 N Atom 3601 CA VAL B 13 70.152 12.432 37.787 1.00 80.92 C Atom 3602 CB VAL B 13 69.025 13.468 37.648 1.00 79.43 C Atom 3603 CG1 VAL B 13 68.935 13.968 36.211 1.00 80.40 C Atom 3604 CG2 VAL B 13 67.701 12.876 38.096 1.00 78.96 C Atom 3605 C VAL B 13 71.487 13.130 37.574 1.00 86.69 C Atom 3606 O VAL B 13 71.894 13.953 38.391 1.00 92.58 O Atom 3607 N PRO B 14 72.178 12.797 36.475 1.00 91.24 N Atom 3608 CA PRO B 14 73.467 13.418 36.153 1.00 88.51 C Atom 3609 CB PRO B 14 73.984 12.570 34.983 1.00 94.58 C Atom 3610 CG PRO B 14 73.156 11.319 34.996 1.00 91.99 C Atom 3611 CD PRO B 14 71.821 11.745 35.511 1.00 94.74 C Atom 3612 C PRO B 14 73.277 14.859 35.702 1.00 87.89 C Atom 3613 O PRO B 14 72.354 15.139 34.936 1.00 92.73 O Atom 3614 N ALA B 15 74.134 15.758 36.174 1.00 86.70 N Atom 3615 CA ALA B 15 74.046 17.164 35.790 1.00 94.92 C Atom 3616 CB ALA B 15 75.253 17.930 36.291 1.00 89.40 C Atom 3617 C ALA B 15 73.911 17.287 34.274 1.00 102.36 C Atom 3618 O ALA B 15 74.413 16.441 33.537 1.00 101.81 O Atom 3619 N GLN B 16 73.235 18.345 33.830 1.00 103.36 N Atom 3620 CA GLN B 16 72.829 18.532 32.434 1.00 110.11 C Atom 3621 CB GLN B 16 73.691 17.716 31.464 1.00 111.20 C Atom 3622 CG GLN B 16 75.082 18.275 31.226 1.00 118.75 C Atom 3623 CD GLN B 16 76.072 17.214 30.779 1.00 121.89 C Atom 3624 OE1 GLN B 16 75.959 16.045 31.153 1.00 111.77 O Atom 3625 NE2 GLN B 16 77.055 17.620 29.981 1.00 120.87 N Atom 3626 C GLN B 16 71.361 18.158 32.265 1.00 114.01 C Atom 3627 O GLN B 16 70.734 17.637 33.188 1.00 110.87 O Atom 3628 OXT GLN B 16 70.769 18.364 31.205 1.00 110.25 O TER 3628 GLN B 16 Atom 3629 O HOH X 1 33.971 37.191 59.197 1.00 42.96 O Atom 3630 O HOH X 2 60.890 41.881 54.164 1.00 52.73 O Atom 3631 O HOH X 3 42.943 31.901 51.275 1.00 57.80 O Atom 3632 O HOH X 4 80.217 34.028 52.049 1.00 69.04 O Atom 3633 O HOH X 5 71.529 22.085 54.618 1.00 69.34 O Atom 3634 O HOH X 6 55.374 44.300 47.226 1.00 58.32 O Atom 3635 O HOH X 7 89.186 24.862 48.284 1.00 54.83 O Atom 3636 O HOH X 8 67.542 39.373 52.710 1.00 54.90 O Atom 3637 O HOH X 9 71.696 23.946 45.242 1.00 62.51 O Atom 3638 O HOH X 10 65.491 31.002 61.081 1.00 61.14 O Atom 3639 O HOH X 11 33.792 43.942 62.464 1.00 59.22 O Atom 3640 O HOH X 12 63.784 48.427 54.556 1.00 70.99 O Atom 3641 O HOH X 13 31.711 43.270 60.900 1.00 61.88 O Atom 3642 O HOH X 14 67.983 34.807 44.140 1.00 53.64 O Atom 3643 O HOH X 15 47.385 38.276 50.237 1.00 60.26 O Atom 3644 O HOH X 16 70.805 23.777 39.744 1.00 76.06 O Atom 3645 O HOH X 17 49.291 52.769 66.147 1.00 71.24 O Atom 3646 O HOH X 18 57.344 23.870 56.441 1.00 59.28 O Atom 3647 O HOH X 19 44.196 23.786 49.444 1.00 77.54 O Atom 3648 O HOH X 20 31.998 40.376 36.462 1.00 80.67 O Atom 3649 O HOH X 21 61.261 45.024 42.557 1.00 79.17 O Atom 3650 O HOH X 22 34.781 34.919 59.258 1.00 60.80 O Atom 3651 O HOH X 23 74.429 25.531 55.372 1.00 66.35 O Atom 3652 O HOH X 24 56.574 56.076 61.857 1.00 69.28 O Atom 3653 O HOH X 25 28.615 46.523 45.185 1.00 72.19 O Atom 3654 O HOH X 26 44.747 19.002 48.920 1.00 82.19 O Atom 3655 O HOH X 27 60.616 51.821 45.702 1.00 79.45 O Atom 3656 O HOH X 28 59.699 34.062 33.466 1.00 77.19 O Atom 3657 O HOH X 29 45.829 27.468 49.150 1.00 70.04 O Atom 3658 O HOH X 30 36.247 28.654 58.224 1.00 76.34 O Atom 3659 O HOH X 31 68.008 35.619 37.743 1.00 64.75 O Atom 3660 O HOH X 32 52.447 44.997 68.769 1.00 72.18 O Atom 3661 O HOH X 33 36.213 54.780 55.326 1.00 85.33 O Atom 3662 O HOH X 34 47.914 22.619 51.309 1.00 84.11 O Atom 3663 O HOH X 35 54.918 32.204 57.781 1.00 64.17 O Atom 3664 O HOH X 36 61.845 33.920 64.510 1.00 67.39 O Atom 3665 O HOH X 37 67.162 41.308 50.608 1.00 71.57 O Atom 3666 O HOH X 38 50.751 50.751 67.297 0.50 62.87 O Atom 3667 O HOH X 39 85.278 17.345 52.387 1.00 84.03 O Atom 3668 O HOH X 40 34.501 30.005 70.141 1.00 59.50 O Atom 3669 O HOH X 41 43.141 44.745 34.218 1.00 85.92 O Atom 3670 O HOH X 42 33.993 32.602 58.111 1.00 64.89 O Atom 3671 O HOH X 43 65.773 33.965 37.223 1.00 67.60 O Atom 3672 O HOH X 44 60.285 51.332 64.243 1.00 87.73 O Atom 3673 O HOH X 45 62.634 30.619 35.680 1.00 79.46 O Atom 3674 O HOH X 46 34.258 32.163 49.588 1.00 77.27 O Atom 3675 O HOH X 47 46.058 35.320 62.696 1.00 55.79 O Atom 3676 O HOH X 48 60.642 49.738 50.534 1.00 75.21 O Atom 3677 O HOH X 49 88.202 22.541 48.912 1.00 61.86 O Atom 3678 O HOH X 50 43.811 28.972 59.258 1.00 77.13 O Atom 3679 O HOH X 51 62.053 48.564 52.574 1.00 64.85 O Atom 3680 O HOH X 52 67.277 −6.429 25.096 1.00 94.62 O Atom 3681 O HOH X 53 47.473 9.209 37.903 1.00 80.97 O Atom 3682 O HOH X 54 63.473 47.031 39.930 1.00 84.21 O End

Polymerase subunit PA protein derived from avian H5N1 influenza virus strains A/goose/Guangdong/1/96 is compared with PA protein sequences of type A influenza virus strains A/BrevigMission/1/1918 that outbreaks on a large scale in Europe, 1998, and two types of type B influenza virus strains B/Ann Arbor/1/1966 and type C influenza virus strains C/JJ/1950, the results of which are as shown in FIG. 1.

PA is divided by the inventor into two parts, and multiple fragments of varying lengths of two parts of a PA gene are cloned and expressed in Escherichia coli, wherein residues 1-256 (see FIG. 1 and FIG. 2) and residues 257-716 (see FIG. 4A) of the N-terminal of PA are well expressed and purified by being fused with GST (Glutathione S-Transferase) and a well-diffracted parental crystal of purified PA amino-terminal (PA_N) is obtained (see FIG. 3).

A preliminary crystallization experiment shows that the C-terminal of PA fails to obtain a crystal despite a lot of efforts has been made. Therefore, the inventor also uses a GST fusion method to express PB1 N-terminal peptides of 25 amino acids and 48 amino acids (see FIG. 4A, which is an electrophoretogram before and after the C-terminal of PA is fused with the GST or the N-terminal of PB1 is fused with the GST, wherein strand 1 PA_C CT is a control sample for the C-terminal of PA, strand 2 GST-PB1+PA_(C) is a sample in which the complex of the C-terminal of PA and the N-terminal of PB1 is fused with GST, strand 3 GST-PB1 is a sample in which the PB1_(N) terminal is fused with GST, strand 4 GST+PA_C is a sample in which the C-terminal of PA is fused with GST, and strand 5 GST CT is a GST control sample; wherein PA_C denotes an electrophoretic band of PA_C, GST-PB1 is an electrophoretic band in which the PB1_(N) terminal is fused with GST, and GST is a control electrophoretic band for GST). The results show that: GST-PB1 can bind to purified PA_C protein.

The in vitro binding experiment shows that the expressing bacterium of the corresponding polypeptides of PA and PB1 are mixed in proportion, and then these two proteins are co-purified through the Glutathione affinity columnand gel exclusion chromatograph, and so on. It is determined therefrom that the co-purification of the two can be realized, indicating the purified 460 amino acids of the C-terminal of PA may form a stable complex with the GST-PB1 polypeptide.

Further, the PA_(C)/PB1_(N) polypeptide complex is separated and purified after using protease to cleave the GST fusion peptide and then used in a crystallization experiment to obtain a crystal under multiple conditions, wherein a well-diffracted crystal is obtained under one condition. However, the separately purified PA C-terminal protein fails to obtain a crystal, implying that the addition of PB1 polypeptide helps to stabilize the PA protein.

Three-Dimensional Structure of PA_(C)/PB1_(N) Polypeptide Complex

A method of MAD is used to analyze a crystal structure of a complex of PA C-terminal 460 amino acids and PB1 N-terminal 25 amino acids, wherein the resolution is 2.9 Angstrom, the finally corrected R factor is 23%, and the R_(free) factor is 26%. In general, if the structure is indicated by lines, the PA part is, vividly speaking, like a wolf's head viewed from the side, which has an extruding mouth, a skull thereafter and a ringed neck (FIG. 4B). PB1 is like a bone bite by the mouth of PA. The PA part mainly consists of 13 α helixes, one small 3₁₀ helix, 7 β sheets and loops connected the preceding structures (FIGS. 1, 4B, and FIG. 5). In terms of structure, the PA protein part can be deemed to have two domains. One domain is an area binding to the PB1 polypeptide (domain I, viz. the first part of the PA C-terminal structure) and is composed of helixes and loops, wherein helixes 4, 5, 8, 9, 10, 11, 12, and 13 constitute the mouth and cheek parts of the wolf's head. Such a domain is relative narrow viewed from the top part of the wolf's head. The other domain (domain II, viz. the second part of the PA C-terminal structure) is a latter half part of the wolf's head composed of the remaining helixes and β sheets, which is relatively large viewed from the top, with a large loop connected below, and resembles the neck part of the wolf' head. The N-terminal of the PB1 polypeptide is located on the side surface of the wolf's head, and the C-terminal is located at the other side surface, which are equivalent to two check sides of the wolf's head. PA of the crystal in the present invention is a polypeptide with the PA N-terminal 256 residues removed. It is reported that the N-terminal is a main active area of PA protease, while the other relative far active site Ser624 is located on the other check side. It is thought that Ser624 is an amino acid of the PA protease active centre which constitutes a protease active area together with the removed part of PA. Therefore, the PA N-terminal removed part is located on the other side surface of the cheek. The second domain of the latter half part of the wolf's head is composed of the remaining helixes and β sheets. Seven differently oriented β sheets of varying lengths constitute a slight twisted plane and located in the center position of the domain, while α helixes are distributed at the periphery of the helix and constitute a Rossmann fold structure. There is a large groove at the junction of two domains to form a large loop about 25 Angstrom in diameter with the lower cervical ring (FIG. 5).

Interaction Between PA and PB1 Polypeptide

Helixes binding to the PB1 polypeptide in domain I are helix 4 (406-415), 8 (582-604aa), (633-650aa), 11 (653-674aa), and 13 (698-714aa), wherein three helixes (8, 11, 13) extend outwards nearly in parallel to form a nearly right-angled triangle viewed from α helix axis direction, the fourth helix (10) extends obliquely, the PB1 polypeptide is interposed therebetween (FIG. 5 and FIG. 6), and helix 4 interacts with the PB1_(N) peptide residue on the side surface. Four helixes forms a hydrophobic core in a region binding to the PB1 polypeptide, and the side chains thereof and the hydrophobic amino acid residues of PB1 are combined together by means of hydrophobic interaction and hydrogen bonds. The second-position aspartic acid to the fifteenth-position glutamine of the PB1 polypeptide can be observed in an electron density map. Such a result coincides with the previous 12 amino acids of the PB1_(N) terminal are key amino acids for PA binding to PB1 reported by Perez, etc. (Perez and Donis 2001). Further, the inventors analyze interaction between these amino acid residues and PA. The conserved LLFL peptide fragment of PB1 reported by the articles of Perez, etc. (Perez and Donis 2001) is present in a short helix and suspended in the middle of the hydrophobic core formed by PA. The amino acid residues of PA involved in forming the hydrophobic core are Leu666 of helix 11, Phe710 of helix 13, and Ile 633, Val636, and Leu640 of helix 10, etc. The amino acids of PA involved in binding to the PB1 polypeptide include Trp706 of helix 13, Gln670 of helix 11, etc., wherein Trp706 interacts with amino acids of Val3, N4, etc. of the PB1 short peptide by means of hydrophobic bonds, van der Waals forces, etc. Gln670 interacts with F9, V12, P13 and A14 of PB1 by means of hydrogen bonds, hydrophobic bonds, van der Waals forces, etc. T639 of helix 10 is involved in the interaction with Val3 (van der Waals forces). Q408 and N412 of helix 4 are involved in the reaction with Val3 and D2 of PB1. In addition, a loose loop interposed between helix 9 and helix 10 is also involved in the interaction with PB1, wherein 1621, G622, and E623 interact with D2 and N5, respectively, and T618 and P620 interact with L8 and K11, respectively. Helix 8 is distant from the PB1 polypeptide, mainly due to van der Waals forces. Such a result is substantially consistent with the function of the residues of the PB1 polypeptide being involved in binding reported by the documents. These amino acids involved in binding to PA are conserved across type A, B and C influenza viruses, and the PA residues involved in binding to the PB1 polypeptide are mostly conserved (FIG. 1). The analysis of a fine three-dimensional structure of a mode of binding PA to PB1 provides a powerful three-dimensional information platform for designing corresponding medicaments to inhibit the function of the influenza virus polymerase.

It is found from the results of analyzing the PA structure that a large groove (domain III) is provided at the conjunction of two domains below domain I (FIG. 8A). The surface of the large groove is enriched with basic amino acids, wherein some amino acids, such as K536, K328, R566, and so on, are highly conserved in the three types of influenza viruses. In addition, the 399th-position Lys and 401st-position Arg are also conserved (FIG. 1). Mutants at the sites of K536 and so on prove the importance of these sites, indicating that the large groove part is associated with the binding of nucleotide or RNA. In addition, a large annular chain part is provided below the groove. This fragment of polypeptide is formed by being pulled apart via interaction between the annular polypeptide fragment with another neighboring molecular surface in crystal packing. The electron density of part of amino acids can not be observed clearly. The large groove and the neck ring constitute a large loop about 25 Angstrom in diameter, and such a space is enough to accommodate a double RNA helix. As described above, on the surface of the groove inside the ring, there are mainly distributed conserved basic amino acids. Although the amino acids of the chain fragment are not highly conserved, the three types of influenza viruses are mainly composed of acidic amino acids. The conservativeness and structure specificity of the groove and the annular structure in the PA molecule imply their critical roles in the polymerase to make them become second drug targets besides the area in which PA binds to PB1.

RNA promoter binding capacity. In terms of the structure analyzed by the inventors, the inventors find that the large groove is a binding site for nucleotide or RNA, wherein the sites of K539, E538, and K328 are highly conserved across the three types of influenza viruses. The inventors deem that these amino acids are involved in binding to RNA nucleotide, especially in binding to RNA, indicating that the PA subunit plays an important role in binding to a promoter, RNA, and a process of RNA synthesis.

Between domain I and domain II, the helixes of domain I and the β sheets of domain II form a channel with a diameter of about 8 Angstrom to 15 Angstrom (FIGS. 8B and 8C). In such a structure analyzed by the inventors, one loose fragment of the N-terminal of PA resembles a rope lying in the channel. Since the N-terminal fragment is relatively far from the two ends of the channel, the inventors think that the N-terminal fragment is absent from the channel when the polymerase complex interacts with other host proteins to exhibit the polymerase's function. Thus, a channel is present in the middle of the domain, extending through the channel from the PA groove to the other side of the cheek of the wolf's head. On the surface of the channel, there exist some amino acids which are highly conserved in the three types of influenza viruses, e.g. R566, K539, and K574 located on the surface of the large groove, conserved E410, K460, E524, and K536 in the middle of the channel, and the like. It is found that some residues thereof have an influence on the polymerase activity. The researches of Fodor, etc. indicate that mutation of E524A abolishes the virus's capacity of RNA synthesis to inhibit virus production. Mutation of E410 decreases the polymerase activity (Fodor, Crow et al. 2002). Mutation of K539A is found not to influence mRNA synthesis but significantly influence gene replication of cRNA and vRNA, indicating that such an area is critical for replication of viral genome. It is known that the nucleotide has a size close to that of the channel (e.g. ATP has a length of about 14 Angstrom and a width of about 8 Angstrom, and other three nucleotides UCG have a size similar thereto). The inventors, thus, deem that such a channel allows the passage of nucleotide or other small molecules or interaction with other proteins in some cases. Therefore, the mutation of the surface residues will cause significant change of the polymerase activity. The unique structure and the functional importance of the channel make it become a third drug designing site for binding target.

In a specific embodiment, there is provided in the present invention a polypeptide, a protein, an inorganic compound, or an organic compound competing with the influenza virus polymerase PB1 to bind to PA_(C), wherein the amino acid sequences of the polypeptide or protein contain a short LLFL motif of the short helix region formed by the PB1_(N) residues 5 to 11 of wild type influenza virus polymerase PB1.

Herein, part of atoms between Met595 and Val12, between Leu666 and Phe9, between Leu640 and Leu8, between Leu636 and Leu8, between Met628 and Leu7, between Phe710 and Thr6, between Trp706 and Thr6, between Trp706 and Pro5, between Phe411 and Pro5, and between Trp706 and Asn4 are involved in interaction within the scope of 4 Angstrom. Therefore, it can be seen that they bind to one another by means of hydrophobic interaction. Thus, polypeptides or compounds involved in hydrophobic interaction with the corresponding amino acids of the C-terminal of PA can be used as medicaments for inhibiting influenza virus.

There are many successful examples for designing a medicament based on a structure of target protein (Schneider, G. and Fechner, U., Nature Reviews Drug Discovery 2005, 4, 649). The LigBuilder program developed by the research group set up by Professor Lu Hua from Peking University has more than 700 worldwide registration users (Wang, R. X.; Gao, Y.; Lai, L. H., LigBuilder: A multi-purpose program for structure-based drug design. J. Mol. Mod. 2000, 6, 498). Many examples has been reported of designing a highly active inhibitor successfully using the LigBuilder program, for example, the Boehringer Ingelheim pharmaceutical company uses LigBuilder 1.2 to access and implement aided design for optimizing a highly active kinase inhibitor (Goldberg D R, Hao, M-H., et al., J. Med. Chem. 2007, 50, 4016).

Novel medicament design and calculation is conducted using the LigBuilder 2.0 program according to the crystal structure of the PAC-PB1N complex of the H5N1 virus RNA polymerase. First, directed at the PAC protein, an analysis of binding sites is made, wherein two binding sites wining highest scores are located in the “mouth” region and the “channel” region of the structure. Novel medicament design and calculation for these two sites are conducted using the LigBuilder 2.0 program to obtain some easily-synthesized compounds with high prediction activity.

Molecules binding to the “channel” region of the PA molecules are exemplified as follows:

R₁=—CH₃, —CH₂CH₃

R₂=—CH₃, —CH₂NH₂, —CH(OH)CH₃, —CH(CH₃)₂

Predicted Kd: 8.64 to 9.60

R₁=—NH₂

R₂=—COCH₃, —CH₂COCH₃, —CO, —OCH₂CH₃

R₃=—CH₂NH₂, —CH₂(NH₂)CH₂CH₃, —CH₂(NH₂)CH₂CH₂CH₃

Predicted Kd: 8.51 to 9.65

Molecules binding to the “mouth” region of the PA molecule are exemplified as follows:

R₁=—OH

R₂=—OH, —CO, —CONH₂, —CONHCH₃, COOH

R₃=—COOH, —NH₂, —C(NH₂)²⁺

R₄=—CH(OH)CH₃, CONH₂, CH(NH₂)CH₂OH

Predicted Kd: 8.52 to 8.96

R₁=—OH, —NHCO

R₂=—CH₂(OH)CH₃, —NHCH₃, —CH₂OH, —CH₂NH₂, —NH₂, —C(NH₂)²⁺

R₃=—NH₂, —C(NH₂)²⁺, —CH₂OH, —CO, —CH₂CO, —NHCO

R₄=—OH, —OCH₃

REFERENCE

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1. Crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein the C-terminal of the influenza virus polymerase subunit PA-PAc is amino acid fragment from amino acid positions about 201˜ about 301 to about 650˜ terminal, the N-terminal of influenza virus polymerase subunit PB1-PB1_(N) is short peptide within the 48 amino acids of the N-terminal of influenza virus polymerase subunit PB1-PB1_(N), wherein atoms of the Crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has at least 40% atomic coordinates listed in table 1, or atomic coordinates of main chain carbon backbone of at least 40% amino acids in the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to the atomic coordinates listed in table
 1. 2. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 1, wherein the influenza virus selects from influenza virus A, B and C type, wherein the influenza virus preferably selects from influenza virus A type: A/goose/Guangdong/1/96, A/Brevig Mission/1/1918; influenza virus B type: B/Ann Arbor/1/1966 or influenza virus C type: C/JJ/1950.
 3. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 1, wherein the crystal of the complex has spacegroup of P4(1)2(1)2, parameter of the crystal is about: a=b=122 Angstrom, c=133 Angstrom, α=β=γ=90°.
 4. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 2, wherein the C-terminal of influenza virus A polymerase subunit PA-PAc consists of the first portion and the second portion, wherein the first portion consists of α helix 4, i.e. amino acids fragment of 406-414 positions, α helix 5, i.e. amino acids fragment of 440-450 positions, α helix 8, i.e. amino acids fragment of 583-603 positions, α helix 9, i.e, amino acids fragment of 608-613 positions, α helix 10, i.e. amino acids fragment of 633-649 positions, α helix 11, i.e. amino acids fragment of 653-673 positions, α helix 12, i.e. amino acids fragment of 683-691 positions, α helix 13, i.e. amino acids fragment of 698-714 positions, β sheet 8, i.e. amino acids fragment of 619-623 positions and β sheet 9, i.e. amino acids fragment of 628-631 positions; wherein the second portion mainly consists of p sheet 1, i.e. amino acids fragment of 290-292 positions, β sheet 2, i.e. amino acids fragment of 317-324 positions, β sheet 3, i.e. amino acids fragment of 480-491 positions, β sheet 4, i.e. amino acids fragment of 496-506 positions, β sheet 5, i.e. amino acids fragment of 517-526 positions, β sheet 6, i.e. amino acids fragment of 541-550 positions and β sheet 7, i.e. amino acids fragment of 557-571 positions; wherein the β sheets of the second portion of the C-terminal of PA-PAc is surrounded by α helix 1, i.e. amino acids fragment of 303-311 positions, α helix 2, i.e. amino acids fragment of 331-349 positions, α helix 3, i.e. amino acids fragment of 364-369 positions, α helix 6, i.e. amino acids fragment of 454-475 positions and α helix 7, i.e. amino acids fragment of 572-578 positions, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIGS. 10A, FIGS. 10B respectively.
 5. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 2, wherein the C-terminal of influenza virus A polymerase subunit PA-PAc interacts with N-terminal of PB1-PB1_(N) mainly through α helix 8, α helix 10, α helix 11 and α helix 13, preferably through at least one amino acid selected from group consisting of Leu666 of α helix 11, Phe710 of α helix 13, Val636 of α helix 10, Leu640 of α helix 10, Trp706 of α helix 13 and Gln670 of α helix 11, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIGS. 10B respectively.
 6. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 2, wherein at least one amino acid selected from the group consisting of Ile621, Gly622, Glu623, Thr618 and Pro620 interacts with the influenza virus polymerase subunit PB1, the Ile621, Gly622, Glu623, Thr618 and Pro620 is in the ring peptide between α helix 9 and α helix 10 of C-terminal of influenza virus A polymerase subunit PA-PAc, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIGS. 10B respectively.
 7. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 2, wherein at least one amino acid selected from the group consisting of Asn647, Gln408, Cys584, Gln587, Gln591, Lys643, Asn647, Ser659, Lys663, Trp699 and Asn703 of the C-terminal of influenza virus A polymerase subunit PA-PAc constitutes “pocket” structure which interacts with the influenza virus polymerase subunit PB1_(N), wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIGS. 10B respectively.
 8. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 2, wherein at least one amino acid selected from the group consisting of Trp406, Glu410, Lys461, Glu524, Phe525, Ser526, Lys536, Lys539, Tyr540, Leu563, Tyr564, Arg566 and Lys574 of the C-terminal of influenza virus A polymerase subunit PA-PAc constitutes “big groove” and “channel” structures which bind to nucleotide, RNA or other small molecular or proteins, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIGS. 10B respectively.
 9. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 2, wherein amino acids of 370˜405 positions of the C-terminal of influenza virus A polymerase subunit PA-PAc constitutes a big ring, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIGS. 10B respectively.
 10. The crystal of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 4, wherein α helix 12 and α helix 13 of C-terminal of influenza virus polymerase subunit PA-PAc interact with other proteins, preferably at least one amino acid selected from the group consisting of Ile690, Glu691, Glu692, Cys693 and Asn696 of the α helix 12 and α helix 13 interacts with other proteins, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIG. 10B respectively.
 11. The crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 4, wherein at least one amino acid selected from the group consisting of Lys506, Gly507, Arg508, Ser509, His510, Leu511, Arg512, Asn513 and Asp514 of the C-terminal of influenza virus A polymerase subunit PA-PAc interacts with other proteins, wherein His510 constitutes portion of the polymerase complex RNase, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIGS. 10B respectively.
 12. Polypeptide, protein, inorganic compound or organic compound binding to at least one member selected from the group consisting of α helix 8, α helix 10, α helix 11 and α helix 13, wherein the influenza virus preferably select from influenza virus A type: A/goose/Guangdong/1/96, A/Brevig Mission/1/1918; influenza virus B type: B/Ann Arbor/1/1966 or influenza virus C type: C/JJ/1950, wherein the polypeptide, protein, inorganic compound or organic compound preferably bind to the member selected from the group consisting of Leu666 in α helix 11, Phe710 in α helix 13, Val636 and Leu640 in α helix 10, Trp706 in α helix 13, Gln670 in α helix 11, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIG. 10B respectively. 13-14. (canceled)
 15. Polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates binding to at least one amino acid selected from the group consisting of Trp406, Glu410, Lys461, Glu524, Phe525, Ser526, Lys536, Lys539, Tyr540, Leu563, Tyr564, Arg566 and Lys574 of the C-terminal of influenza virus A polymerase subunit PA-PAc, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIGS. 10B respectively. 16-19. (canceled)
 20. Polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates binding to PAc competed with influenza virus polymerase subunit PB1, wherein the polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates mainly interact with PAc through the hydrophobic core constituted by the α helix 8, α helix 11, α helix 13 and α helix 10, preferably interact with PAc through Met595 in α helix 8, Leu666 in α helix 11, Trp706 and Phe710 in α helix 13, Val636 and Val640 in α helix 10, wherein amino acids positions of corresponding fragments of influenza virus B and C type are shown in FIGS. 1A, 1B, 1C and FIG. 10A and FIGS. 10B respectively.
 21. Polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates binding to PAc competed with influenza virus polymerase subunit PB1 of claim 20, wherein the amino acid sequence of the polypeptide or protein comprises at least three amino acids which is the same in corresponding position of short PTLLFL motif of the short helix domain constituted by the 5th˜10th residues Pro5, Thr6, Leu7, Leu8, Phe9 and Leu10 of N-terminal of wild influenza virus polymerase subunit PB1-PB1_(N), when the polypeptide or protein is aligned with the PTLLFL motif. 22-23. (canceled)
 24. A method of expression and purifying of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), include: (a) Construct carrier of gene sequence encoding amino acid positions about 201˜ about 301 to about 650˜ terminal of the C-terminal of influenza virus polymerase subunit PA-PAc, a tag protein fuse or not fuse to the carrier, prokaryotic cells or eukaryotic cells are transformed with said carrier in order to express the PAc with the tag protein; (b) A method similar with that of expressing PAc was used to express the PB1_(N) with or without tag protein; (c) Proportional mix the influenza virus polymerase subunit PAc-expressing cell obtained from step (a) and the 48 amino acids within the N-terminal of influenza virus polymerase subunit PB1-expressing cell obtained from step (b), the resulted protein is separated through the specifically binding with the specific tag, the tag protein is removed from the protein through enzymolysis, the complex of PAc and PB1_(N) is separated, the concentration of the complex is determined; Wherein the atoms of the Crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has at least 40% atomic coordinates listed in table 1, or atomic coordinates of main chain carbon backbone of at least 40% amino acids in the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) has average root mean square deviation smaller than or equal to 1.7 Angstrom with respect to the atomic coordinates listed in table
 1. 25. The method of expression and purifying of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 24, wherein the tag protein selects from GST, Flag-tag, Myc-tag, MBP-tag, specific antibody; the carrier includes selective tag gene, the Proportional mixing in step (c) is mean that molar ratio of tag protein-PAc and tag protein-PB1_(N) is 0.1:1˜1:0.1, preferably the molar ratio of tag protein-PAc and tag protein-PB1_(N) is 0.5:1˜1:0.5, more preferably the molar ratio of tag protein-PAc and tag protein-PB1_(N) is nearly 1:1, more preferably the tag protein is GST, the method recognizing the specific tag is performed through affinity column, the method of removing tag is preformed by proteinases, the method of separating the complex of PAc and PB1_(N) is preformed through gel filtration or ion-exchange chromatography, the determining of concentration of protein is preformed through gel electrophoresis.
 26. The method of expression and purifying complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) of claim 25, wherein the prokaryotic cell is Escherichia coli.
 27. Method of cocrystallize the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N), include: the protein concentration of the purified complex of PAc and PB1_(N) is condensed to 5-30 mg/ml; the crystal growth condition is screened by gas sitting drop and hanging drop; crystal of the complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) is obtained. 28-34. (canceled)
 35. Use of the crystal three-dimensional structure of complex of C-terminal of influenza virus polymerase subunit PA-PAc and N-terminal of influenza virus polymerase subunit PB1-PB1_(N) in designing and screening polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates used in the treatment of diseases caused by the influenza virus infection, include: design polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates binding to specific portion through computer stimulation technology according to coordinates of three-dimensional structure of protein; search for polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates binding to specific portion through computer stimulation technology according to coordinates of three-dimensional structure of the protein; the designed or searched polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates according to coordinates of three-dimensional structure of the protein bind to any type of influenza virus polymerase protein which have at least 50% sequence identity with the PAc and the PB sequence, binding information is then analysed; the designed or searched polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates according to coordinates of three-dimensional structure of the protein bind to any type of influenza virus polymerase protein which have at least 50% sequence identity with the PAc and the PB1_(N) sequence, and then crystallization is preformed, the binding information of polypeptide or compound molecular to protein is analysed through crystal diffraction method; wherein the polypeptide, protein, inorganic compound or organic compound, antibody or immune conjugates that bind to any type of influenza virus polymerase protein which had at least 50% sequence identity with the PAc and the PB sequence are candidate compound. 36-43. (canceled) 